Compounds as tyrosine kinase modulators

ABSTRACT

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/054,444, filed on Oct. 15, 2013, which is a continuation of U.S.application Ser. No. 12/875,218, filed on Sep. 3, 2010, which claims thebenefit of U.S. Provisional Application Nos. 61/239,603, filed on Sep.3, 2009, 61/306,616, filed on Feb. 22, 2010, 61/356,699 filed on Jun.21, 2010 and 61/360,531 filed on Jul. 1, 2010, all of each which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to novel compounds with multiplearomatic components capable of modulating, regulating and/or inhibitingtyrosine kinase signal transduction. The present invention is alsodirected to methods of prevention and/or treatment of disorders relatedto unregulated tyrosine kinase signal transduction, including but notlimited to, cell growth disorders, metabolic disorders, blood vesselproliferative disorders, inflammatory disorders, neurodegenerativediseases and immune disorders.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (“PTKs”) play an important role in the controlof cell growth and differentiation. PTKs comprise a large and diverseclass of proteins having enzymatic activity. PTKs can be of thereceptor-type (having extracellular, transmembrane and intracellulardomains) or the non-receptor type (being wholly intracellular). Forexample, signal transduction mediated by receptor tyrosine kinases(“RTKs”) is initiated by extracellular interaction with a specificgrowth factor (i.e., a ligand), followed by receptor dimerization,transient stimulation of the intrinsic protein tyrosine kinase activityand phosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolichomeostasis, and responses to the extracellular microenvironment).

With respect to RTKs, it has been shown also that tyrosinephosphorylation sites function as high-affinity binding sites for SH2(src homology) domains of signaling molecules. Several intracellularsubstrate proteins that associate with RTKs have been identified and aredivided into two principal groups: (1) substrates which have a catalyticdomain; and (2) substrates which lack a catalytic domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors or proteins and SH2domains of their substrates is determined by the amino acid residuesimmediately surrounding the phosphorylated tyrosine residue. Differencesin binding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each RTK is determined not only by its pattern of expression andligand availability, but also by the array of downstream signaltransduction pathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

The RTKs comprise a large family of transmembrane receptors with diversebiological activities. The intrinsic function of RTKs is activated uponligand binding, which results in phophorylation of the receptor andmultiple cellular substrates, and subsequently in a variety of cellularresponses. At present, at least nineteen distinct RTK subfamilies havebeen identified. One RTK subfamily, designated the HER subfamily, isbelieved to be comprised of EGFR, HER2, HER3 and HER4. Ligands to theHER subfamily of receptors include epithelial growth factor (EGF),TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. The secondsubfamily of RTKs, designated the insulin subfamily, is comprised of theINS-R, the IGF-1R and the IR-R. The third RTK subfamily, the “PDGF”family, includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the kinase insert domain-receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to be areceptor for hematopoietic growth factors. Two other subfamilies of RTKshave been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 andFGFR4) and the Met subfamily (c-met and Ron). Because of thesimilarities between the PDGF and FLK subfamilies, the two subfamiliesare often considered together. The known RTK subfamilies are identifiedin Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated hereinby reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps,Fak, Jak, Ack and LIMK) have been identified. At present, the Srcsubfamily of non-receptor tyrosine kinases is comprised of the largestnumber of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr andYrk. The Src subfamily of enzymes has been linked to oncogenesis. A moredetailed discussion of non-receptor tyrosine kinases is provided inBolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein byreference.

Many of the protein tyrosine kinases (PTKs), whether an RTK ornon-receptor tyrosine kinase, have been found to be involved in cellularsignaling pathways leading to cellular signal cascades and pathogenicconditions such as cancer, psoriasis and hyper immune responses. In viewof the importance of PTKs to the control, regulation and modulation ofcell proliferation and the diseases and disorders associated withabnormal cell proliferation, many attempts have been made to identifyreceptor and non-receptor tyrosine kinase “inhibitors” using a varietyof approaches, including the use of mutant ligands (U.S. Pat. No.4,966,849), soluble receptors and antibodies (Kendall & Thomas, 1994,Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362:841-844), RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56);Takano, et al, 1993, Mol. Bio. Cell 4:358 A; Kinsella, et al, 1992, Exp.Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152:448-57) and tyrosine kinase inhibitors (U.S. Pat. No. 5,330,992;Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).

More recently, attempts have been made to identify small molecules whichact as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclicor heterocyclic aryl compounds (PCT Application No. WO 92/20642),vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have beendescribed generally as tyrosine kinase inhibitors. Styryl compounds(U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S.Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No.0 566 266 A1), seleoindoles and selenides (PCT Application No. WO94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO92/21660) and benzylphosphonic acid compounds (PCT Application No. WO91/15495) have been described as compounds for use as tyrosine kinaseinhibitors for use in the treatment of cancer.

In addition, other small molecules were studied as tyrosine kinaseinhibitors, such as the compounds disclosed in U.S. Pat. Nos. 6,765,012;6,541,504; 6,747,025; 5,792,783; 5,834,504; 5,883,113; 5,883,116 and5,886,020, all of which are incorporated by reference in theirentireties.

The identification and use of compounds which specifically inhibitsignal transduction by modulating the activity of receptor andnon-receptor tyrosine is one aspect of the present invention.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by Formula Icapable of modulating, regulating and/or inhibiting tyrosine kinasesignal transduction, and uses of the compounds and compositionsincorporating the compounds for disease treatment and prevention.

The compounds of the present invention can be found in general FormulaI:

wherein

-   -   X is selected from the group consisting of NR¹, O, S(O)_(n);    -   n is 0 or an integer of from 1 to 2;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(I) is selected from the group consisting of hydrogen,        halogen, C₁ to C₈ alkyl, S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        O(CR⁵R⁶)_(d)Ar, S(O)_(f)(CR⁵R⁶)_(d)Ar, (CR⁵R⁶)_(d)S(O)_(f)R⁴,        NR⁴(CR⁵R⁶)_(d)S(O)_(f)R⁴, O(CR⁵R⁶)_(d) S(O)_(f)R⁴,        S(O)_(f)(CR⁵R⁶)_(e)S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)N(R⁴)₂,        NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂, O(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)OR⁴, (CR⁵R⁶)_(d)OSO₂R⁴,        S(O)_(f)(CR⁵R⁶)_(e)OSO₂R⁴, (CR⁵R⁶)_(d)P(O)(OR⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)P(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, C(O)N═S(O)R⁵R⁶, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂,        (CR⁵R⁶)_(d)R⁵, S(O)_(f)(CR⁵R⁶)_(d)R⁵, HNC(O)R⁴, HN—C(O)OR⁴,        (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f) (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate;    -   a is 0 or an integer of from 1 to 3;    -   d is 0 or an integer of from 1 to 5;    -   e is an integer of from 1 to 4;    -   f is 0 or an integer of from 1 to 2;    -   R^(II) is independently selected from the group consisting of        hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy,        aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,        hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl,        (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl,        wherein R² and R³ are independently selected from the group        consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,        arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;        alternatively R² and R³ and may be taken together to form a 5-7        membered heterocyclic ring with N;    -   b is 0 or an integer of from 1 to 2;        Y is selected from the group consisting of:    -   (1′) —(CH₂)g-O—(CH₂)h-;    -   (2′) —(CH₂)g-NR′—(CH₂)h-;    -   (3′) —(CH₂)g-S(O)_(n)—(CH₂)h-;    -   (4′) —(CH₂)g-SO₂NR²—(CH₂)h-;    -   (5′) —(CH₂)g-NR²SO₂—(CH₂)h-;    -   (6′) —(CH₂)g-CO—(CH₂)h-;    -   (7′) —(CH₂)g-C(O)NR²—(CH₂)h-;    -   (8′) —(CH₂)g-NR²C(O)—(CH₂)h-;    -   (9′) —(CH₂)g-C≡C—(CH₂)h-;    -   (10′) —(CH₂)g-NR²C(O)NR³—(CH₂)h-;    -   (11′) —(CH₂)g-(CH₂)h-;    -   (12′) —(CH₂)g-CF₂—(CH₂)h-;    -   (13′) —(CH₂)g-CCl₂—(CH₂)h-;    -   (14′) —(CH₂)g-CHF—(CH₂)h-;    -   (15′) —(CH₂)g-CH(OH)—(CH₂)h-;    -   (16′) —(CH₂)g-CR²R³—(CH₂)h-;    -   (17′) —(CH₂)g-C═C—(CH₂)h-;    -   and (18′) a single bond;        wherein        g is 0 or an integer of from 1 to 3;        h is 0 or an integer of from 1 to 3;        R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;

R² and R³ are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternativelyR² and R³ and may be taken together to form a 5-7 membered cyclic ring;

Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6heteroatoms independently selected from the group consisting of O, N andS;Ring A can be illustrated but not limited to the following:

whereinR¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N;R^(III) represents optionally 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;Z is selected from the group consisting of

-   -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁷)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j);    -   wherein    -   i is 0 or 1;    -   j is 0 or 1;    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl.

Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;Ring B can be illustrated but not limited to the following:

whereinR¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N;R^(IV) represents optionally 1-3 substituents, independently selectedfrom the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR⁹R¹⁰; wherein R⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl.

Some embodiments of the present invention are included in the followingparagraphs:

-   -   (1) A compound according to Formula I, including any tautomer,        stereoisomer, diastereoisomeric form, polymorphic form, crystal        form, a solvate, a hydrate, a metabolite, a pharmaceutically        acceptable salt or prodrug, mixture of different stereoisomers,        and any mixture of different crystal forms.    -   (2) A compound of Formula I in the form of a prodrug.    -   (3) The compound according to paragraph 1, wherein Z is selected        from the group consisting of (CH₂)_(i)N(R⁷)C(O),        C(O)N(R⁸)(CH₂)_(j), (CH₂)_(i)N(R⁷)S(O)₂ and S(O)₂N(R⁸)(CH₂)_(j).    -   (4) The compound according to paragraphs 1-3, wherein Y is        selected from the group consisting of —(CH₂)g-O—(CH₂)h-;        —(CH₂)g-NR¹—(CH₂)h-; —(CH₂)g-S(O)_(n)—(CH₂)h-;        —(CH₂)g-SO₂NR²—(CH₂)h-; —(CH₂)g-NR²SO₂—(CH₂)h-;        —(CH₂)g-CO—(CH₂)h-; —(CH₂)g-C(O)NR²—(CH₂)h-;        —(CH₂)g-NR²C(O)—(CH₂)h-; —(CH₂)g-C≡C—(CH₂)h-;        —(CH₂)g-NR²C(O)NR³—(CH₂)h and a single bond.    -   (5) The compound according to paragraphs 1-4, wherein Ring A and        Ring B are independently selected from the group consisting of

-   -   (6) The compound according to paragraphs 1-5, wherein Y is        selected from the group consisting of —(CH₂)g-(CH₂)h-;        —(CH₂)g-CF₂—(CH₂)h-; —(CH₂)g-CCl₂—(CH₂)h-; —(CH₂)g-CHF—(CH₂)h-;        —(CH₂)g-CH(OH)—(CH₂)h-; —(CH₂)g-CR²R³—(CH₂)h-; and        —(CH₂)g-C═C—(CH₂)h-.    -   (7) The compound according to paragraphs 1-6, wherein X is NH.    -   (8) A compound selected from the group consisting of

-   (1′)    [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic    acid;

-   (2′) methyl    [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate;

-   (3′)    ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetic    acid;

-   (4′)    methyl({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetate;

-   (5′)    5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic    acid;

-   (6′) methyl    5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (7′)    5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide;

-   (8′)    4-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

-   (9)    N-(2,3-dihydroxypropyl)-5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide;

-   (10)    N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

-   (11′)    5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide;

-   (12′) methyl    5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (13′)    5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic    acid;

-   (14′)N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

-   (15′)N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

-   (16′)    5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

-   (17′)N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

-   (18′)N-(3-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;

-   (19′)    5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic    acid;

-   (20′) methyl    5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (21′) 2,3-dihydroxypropyl    5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

-   (22′)    5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic    acid;

-   (23′) methyl    5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (24′) 2-hydroxyethyl    5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (25′) 2-hydroxyethyl    5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

-   (26′)    5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic    acid;

-   (27′) methyl    5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

-   (28′)    5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic    acid;

-   (29′) methyl    5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

-   (30′)    N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

-   (31′)    N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;

-   (32′)    5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic    acid;

-   (33′) methyl    5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

-   (34′)    3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide;

-   (35′) methyl    4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate;

-   (36′)    2-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide;

-   and (37′)    3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide.    -   (9) The compound according to paragraph 1, wherein Z is        (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j) or        (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(i), provided that when Ring B is        pyrazole, R^(IV) is not a phenyl or substituted phenyl.    -   (10) The compound according to paragraph 9, wherein Y is        selected from the group consisting of —(CH₂)g-O—(CH₂)h-;        —(CH₂)g-NR¹—(CH₂)h-; —(CH₂)g-S(O)_(n)—(CH₂)h-;        —(CH₂)g-SO₂NR²—(CH₂)h-; —(CH₂)g-NR²SO₂—(CH₂)h-;        —(CH₂)g-CO—(CH₂)h-; —(CH₂)g-C(O)NR²—(CH₂)h-;        —(CH₂)g-NR²C(O)—(CH₂)h-; —(CH₂)g-C≡C—(CH₂)h-;        —(CH₂)g-NR²C(O)NR³—(CH₂)h, and a single bond.    -   (11) The compound according to paragraph 9, wherein Y is        selected from the group consisting of —(CH₂)g-(CH₂)h-;        —(CH₂)g-CF₂—(CH₂)h-; —(CH₂)g-CCl₂—(CH₂)h-; —(CH₂)g-CHF—(CH₂)h-;        —(CH₂)g-CH(OH)—(CH₂)h-; —(CH₂)g-CR²R³—(CH₂)h-; and        —(CH₂)g-C═C—(CH₂)h-.    -   (12) The compound according to paragraphs 9-11, wherein Ring A        and Ring B are independently selected from the group consisting        of

-   -   (13) The compound according to paragraphs 9-12, wherein X is NH.    -   (14) The compound according to paragraphs 9-12, wherein X is S.    -   (15) The compound according to paragraphs 9-14, wherein R^(I) is        selected from the group consisting of hydrogen, halogen, C₁ to        C₈ alkyl, (CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        (CR⁵R⁶)_(d)C(O)N(R⁴)₂, NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        O(CR⁵R⁶)_(d)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, C(O)N═S(O)R⁵R⁶, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂,        (CR⁵R⁶)_(d)R⁵, HNC(O)R⁴, HN—C(O)OR⁴, (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f)        (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate.    -   (16) A compound of Formula II:

wherein

W is C or N;

X is selected from the group consisting of NR¹, O, and S(O)_(n);n is 0 or an integer of from 1 to 2;R¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N;R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate;R^(II) is independently selected from the group consisting of hydrogen,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,(NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and(NR²R³)carbonylalkyl, wherein R² and R³ are independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternativelyR² and R³ and may be taken together to form a 5-7 membered heterocyclicring with N;b is 0 or an integer of from 1 to 2;Y is selected from the group consisting of:

-   -   (1′) —(CH₂)g-O—(CH₂)h-;    -   (2′) —(CH₂)g-NR¹—(CH₂)h-;    -   (3′) —(CH₂)g-S(O)_(n)—(CH₂)h-;    -   (4′) —(CH₂)g-SO₂NR²—(CH₂)h-;    -   (5′) —(CH₂)g-NR²SO₂—(CH₂)h-;    -   (6′) —(CH₂)g-CO—(CH₂)h-;    -   (7′) —(CH₂)g-C(O)NR²—(CH₂)h-;    -   (8′) —(CH₂)g-NR²C(O)—(CH₂)h-;    -   (9′) —(CH₂)g-C≡C—(CH₂)h-;    -   (10′) —(CH₂)g-NR²C(O)NR³—(CH₂)h-;    -   (11′) —(CH₂)g-(CH₂)h-;    -   (12′) —(CH₂)g-CF₂—(CH₂)h-;    -   (13′) —(CH₂)g-CCl₂—(CH₂)h-;    -   (14′) —(CH₂)g-CHF—(CH₂)h-;    -   (15′) —(CH₂)g-CH(OH)—(CH₂)h-;    -   (16′) —(CH₂)g-CR²R³—(CH₂)h-;    -   (17′) —(CH₂)g-C═C—(CH₂)h-;    -   and (18′) a single bond;        wherein    -   g is 0 or an integer of from 1 to 3;    -   h is 0 or an integer of from 1 to 3;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R² and R³ are independently selected from the group consisting        of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl,        alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and        heterocyclylsulfonyl; alternatively R² and R³ and may be taken        together to form a 5-7 membered cyclic ring;        Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6heteroatoms independently selected from the group consisting of O, N andS;Ring A can be illustrated but not limited to the following:

wherein

-   -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(III) represents optionally 1-3 substituents independently        selected from the group consisting of C₁-C₅ linear or branched        alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy,        hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen,        cyano, and nitro;        Z is selected from the group consisting of    -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁷)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j);        wherein    -   i is 0 or 1;    -   j is 0 or 1;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen and alkyl;Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;Ring B can be illustrated but not limited to the following:wherein

-   -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;        R^(IV) represents optionally 1-3 substituents, independently        selected from the group consisting of alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo,        haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and        —NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected from the        group consisting of hydrogen, alkyl, alkylcarbonyl, aryl,        arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and        heterocyclylalkyl;        and any pharmaceutical acceptable salt or prodrug.    -   (17) The compound according to paragraph 16, wherein Z is        selected from the group consisting of (CH₂)_(i)N(R⁷)C(O),        C(O)N(R⁸)(CH₂)_(j), (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j) and        (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j).    -   (18) The compound according to paragraphs 16-17, wherein Y is        selected from the group consisting of —(CH₂)g-O—(CH₂)h-;        —(CH₂)g-NR¹—(CH₂)h-; —(CH₂)g-S(O)_(n)—(CH₂)h-;        —(CH₂)g-SO₂NR²—(CH₂)h-; —(CH₂)g-NR²SO₂—(CH₂)h-;        —(CH₂)g-CO—(CH₂)h-; —(CH₂)g-C(O)NR²—(CH₂)h-;        —(CH₂)g-NR²C(O)—(CH₂)h-; —(CH₂)g-C≡C—(CH₂)h-;        —(CH₂)g-NR²C(O)NR³—(CH₂)h and a single bond.    -   (19) The compound according to paragraphs 16-18, wherein Ring A        and Ring B are independently selected from the group consisting        of

-   -   (20) The compound according to paragraphs 16-19, wherein W is C.    -   (21) A method of use of the compounds of paragraphs 1-20,        wherein the compounds are used as tyrosine kinase modulators;    -   (22) Use of the compounds of paragraphs 1-20 in the preparation        of a medicament for the treatment or prevention of diseases or        conditions related with unregulated tyrosine kinase activities,        comprising administering a therapeutically effective amount of        the compound of paragraphs 1-20 together with a pharmaceutically        acceptable carrier;    -   (23) The use of paragraph 22, wherein the diseases or conditions        are selected from the group consisting of cell growth and        metabolic disorders, blood vessel proliferative disorders,        inflammatory disorders, neurodegenerative diseases, and immune        disorders.    -   (24) The use of paragraphs 22-23 wherein the diseases or        conditions are selected from the group consisting of colorectal        cancer, lung cancer, hematological cancer, renal cancer, liver        cancer, breast cancer, diabetic retinopathy, macular        degeneration, age-related macular degeneration, retinopathy of        prematurity, ocular angiogenesis, retinal edema, retinal        ischemia, diabetic macular edema, cystoid macular edema, retinal        vein occlusion, branch vein occlusion, preretinal        neovascularization, laser-induced choroidal neovascularization,        neovascularization associated with keratoplasty, glaucoma and        ocular tumors, arthritis, restenosis, hepatic cirrhosis,        atherosclerosis, psoriasis, diabetes mellitus, wound healing,        inflammation, neurodegenerative diseases and immune disorders.    -   (25) The use of paragraphs 22-23 wherein the conditions and        diseases are wound healing or to alleviate transplant rejection.    -   (26) A pharmaceutical composition comprising a therapeutic        effective amount of a compound according to paragraphs 1-20        together with a pharmaceutically acceptable carrier which is        suitable for systematic, parenteral, local or topical delivery.    -   (27) The pharmaceutical composition of paragraph 26, which are        in the form selected from the group comprising of tablets,        capsules, intravenous injections, intramuscular injections,        local injections, topical creams, gels and ointments, eye drops,        ophthalmic solutions, ophthalmic suspensions, ophthalmic        emulsions, intravitreal injections, subtenon injections,        ophthalmic biodrodible implant, and non-bioeordible ophthalmic        inserts or depots.    -   (28) Use of the compounds of paragraphs 1-20 in the preparation        of a medicament for the treatment of diseases and conditions,        wherein the medicament contains pharmaceutical acceptable        composition according to paragraphs 26 and 27.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-Ray Diffraction (XRPD) of Example 78;

FIG. 2 shows a powder X-Ray Diffraction (XRPD) of Example 69;

FIG. 3 shows a fluorescein angiography (blood-retinal barrier breakdown)of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75Sodium, Example 69, and Example 66; and

FIG. 4 shows a fundus photography (retinal vasodilation and vesseltortuosity) of Example 121, Example 84 Sodium, Example 83, Example 78,Example 75 Sodium, Example 69, and Example 66.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a series of compounds with multiplearomatic components useful as protein tyrosine kinase inhibitors. Thecompounds of the present invention are useful for treating diseasesrelated to unregulated tyrosine kinase signal transduction, for example,cancer, blood vessel proliferative disorders, fibrotic disorders, andneurodegenerative diseases. In particular, compounds of the presentinvention are useful for the treatment of colorectal cancer, lungcancer, hematological cancer, renal cancer, liver cancer, breast cancer,diabetic retinopathy, macular degeneration, age-related maculardegeneration, retinopathy of prematurity, ocular angiogenesis, retinaledema, retinal ischemia, diabetic macular edema, cystoid macular edema,retinal vein occlusion, branch vein occlusion, preretinalneovascularization, laser-induced choroidal neovascularization,neovascularization associated with keratoplasty, glaucoma and oculartumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, diabetes mellitus, wound healing, transplant rejection,inflammation, neurodegenerative diseases and immune disorders.

1. COMPOUNDS OF THE INVENTION

-   -   In one aspect of the invention, the compounds of the present        invention can be represented by the general formula I:

-   -   wherein    -   X is selected from the group consisting of NR¹, O, and S(O)_(n);    -   n is 0 or an integer of from 1 to 2;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(I) is selected from the group consisting of hydrogen,        halogen, C₁ to C₈ alkyl, S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)C(O)OR⁴, (CR⁵R⁶)_(d)Ar, NR⁴(CR⁵R⁶)_(d)Ar,        O(CR⁵R⁶)_(d)Ar, S(O)_(f)(CR⁵R⁶)_(d)Ar, (CR⁵R⁶)_(d)S(O)_(f)R⁴,        NR⁴(CR⁵R⁶)_(d)S(O)_(f)R⁴, O(CR⁵R⁶)_(d) S(O)_(f)R⁴,        S(O)_(f)(CR⁵R⁶)_(e)S(O)_(f)R⁴, (CR⁵R⁶)_(d)C(O)N(R⁴)₂,        NR⁴(CR⁵R⁶)_(d)C(O)N(R⁴)₂, O(CR⁵R⁶)_(d)C(O)N(R⁴)₂,        S(O)_(f)(CR⁵R⁶)_(e)C(O)N(R⁴)₂, (CR⁵R⁶)_(d)OR⁴,        S(O)_(f)(CR⁵R⁶)_(d)OR⁴, (CR⁵R⁶)_(d)OSO₂R⁴,        S(O)(CR⁵R⁶)_(e)OSO₂R⁴, (CR⁵R⁶)_(d)P(O)(OR⁴)₂,        S(O)(CR⁵R⁶)_(e)P(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_(d)N(R⁴)₂,        C(O)(CR⁵R⁶)_(d)N(R⁴)₂, C(O)N═S(O)R⁵R⁶, NR²C(O)(CR⁵R⁶)_(d)N(R⁴)₂,        (CR⁵R⁶)_(d)R⁵, S(O)_(f)(CR⁵R⁶)_(d)R⁵, HNC(O)R⁴, HN—C(O)OR⁴,        (CR⁵R⁶)_(d)N(R⁴)₂, S(O)_(f) (CR⁵R⁶)_(d)N(R⁴)₂, OC(O)OR⁴,        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)R⁴, (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)OR⁴, and        (CR⁵R⁶)_(d)C(O)(CR⁵R⁶)_(d)N(R⁴)₂, wherein each R⁴ is        independently selected from the group consisting of hydrogen,        hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈        alkoxyalkyl, (CR⁵R⁶)_(d) and N(R⁴)₂ may form a 3-7 membered        heterocyclic ring, comprising of aziridine, azetidine,        pyrrolidine, 5-fluoropyrrolidine, piperidine,        6-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine, and wherein said        heterocyclic ring may be optionally substituted with up to three        of R⁵; wherein R⁵ and R⁶ are independently selected from the        group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈        hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl,        alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide,        alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a        carbocyclic or heterocyclic ring of from 5 to 6 carbons or        alternatively, (CR⁵R⁶)_(d) and (CR⁵R⁶)_(e) may form a 3-7        membered carbocyclic or heterocyclic ring, wherein the ring may        be optionally substituted with up to three of hydroxyl, halo,        C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,        alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,        hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and        sulfonate;    -   a is 0 or an integer of from 1 to 3;    -   d is 0 or an integer of from 1 to 5;    -   e is an integer of from 1 to 4;    -   f is 0 or an integer of from 1 to 2;        R^(II) is independently selected from the group consisting of        hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy,        aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,        hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl,        (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl,        wherein R² and R³ are independently selected from the group        consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,        arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;        alternatively R² and R³ and may be taken together to form a 5-7        membered heterocyclic ring with N;        b is 0 or an integer of from 1 to 2;        Y is selected from the group consisting of:    -   (1′) —(CH₂)g-O—(CH₂)h-;    -   (2′) —(CH₂)g-NR¹—(CH₂)h-;    -   (3′) —(CH₂)g-S(O)_(n)-(CH₂)h-;    -   (4′) —(CH₂)g-SO₂NR²—(CH₂)h-;    -   (5′) —(CH₂)g-NR²SO₂—(CH₂)h-;    -   (6′) —(CH₂)g-CO—(CH₂)h-;    -   (7′) —(CH₂)g-C(O)NR²—(CH₂)h-;    -   (8′) —(CH₂)g-NR²C(O)—(CH₂)h-;    -   (9′) —(CH₂)g-C≡C—(CH₂)h-;    -   (10′) —(CH₂)g-NR²C(O)NR³—(CH₂)h-;    -   (11′) —(CH₂)g-(CH₂)h-;    -   (12′) —(CH₂)g-CF₂—(CH₂)h-;    -   (13′) —(CH₂)g-CCl₂—(CH₂)h-;    -   (14′) —(CH₂)g-CHF—(CH₂)h-;    -   (15′) —(CH₂)g-CH(OH)—(CH₂)h-;    -   (16′) —(CH₂)g-CR²R³—(CH₂)h-;    -   (17′) —(CH₂)g-C═C—(CH₂)h-;    -   and (18′) a single bond.        wherein    -   g is 0 or an integer of from 1 to 3;    -   h is 0 or an integer of from 1 to 3;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;        R² and R³ are independently selected from the group consisting        of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl,        alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and        heterocyclylsulfonyl; alternatively R² and R³ and may be taken        together to form a 5-7 membered cyclic ring;        Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6heteroatoms independently selected from the group consisting of O, N andS;Ring A can be illustrated but not limited to the following:

whereinR¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N.R^(III) represents optionally 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;Z is selected from the group consisting of

-   -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁷)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j);        wherein    -   i is 0 or 1;    -   j is 0 or 1;    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl;        Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;Ring B can be illustrated but not limited to the following:

whereinR¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N;R^(IV) represents optionally 1-3 substituents, independently selectedfrom the group consisting of hydrogen, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR⁹R¹⁰;wherein R⁹ and R¹⁰ are independently selected from the group consistingof hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;In another aspect of the invention, the compounds of the presentinvention can be represented by the general formula II:

wherein

W is C or N;

X is selected from the group consisting of NR¹, O, and S(O)_(n);n is 0 or an integer of from 1 to 2;R¹ is independently selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl,heterocycloalkyl, hydroxyalkyl, and alkyl(NR²R³), wherein R² and R³ areindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R² and R³ andmay be taken together to form a 5-7 membered heterocyclic ring with N;R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl,hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, and sulfonate;R^(II) is independently selected from the group consisting of hydrogen,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,(NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and(NR²R³)carbonylalkyl, wherein R² and R³ are independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternativelyR² and R³ and may be taken together to form a 5-7 membered heterocyclicring with N;b is 0 or an integer of from 1 to 2;Y is selected from the group consisting of:

-   -   (1′) —(CH₂)g-O—(CH₂)h-;    -   (2′) —(CH₂)g-NR¹—(CH₂)h-;    -   (3′) —(CH₂)g-S(O)_(n)—(CH₂)h-;    -   (4′) —(CH₂)g-SO₂NR²—(CH₂)h-;    -   (5′) —(CH₂)g-NR²SO₂—(CH₂)h-;    -   (6′) —(CH₂)g-CO—(CH₂)h-;    -   (7′) —(CH₂)g-C(O)NR²—(CH₂)h-;    -   (8′) —(CH₂)g-NR²C(O)—(CH₂)h-;    -   (9′) —(CH₂)g-C≡C—(CH₂)h-;    -   (10′) —(CH₂)g-NR²C(O)NR³—(CH₂)h-;    -   (11′) —(CH₂)g-(CH₂)h-;    -   (12′) —(CH₂)g-CF₂—(CH₂)h-;    -   (13′) —(CH₂)g-CCl₂—(CH₂)h-;    -   (14′) —(CH₂)g-CHF—(CH₂)h-;    -   (15′) —(CH₂)g-CH(OH)—(CH₂)h-;    -   (16′) —(CH₂)g-CR²R³—(CH₂)h-;    -   (17′) —(CH₂)g-C═C—(CH₂)h-;    -   and (18′) a single bond;        wherein    -   g is 0 or an integer of from 1 to 3;    -   h is 0 or an integer of from 1 to 3;    -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R² and R³ are independently selected from the group consisting        of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl,        alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and        heterocyclylsulfonyl; alternatively R² and R³ and may be taken        together to form a 5-7 membered cyclic ring;        Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5heteroatoms independently selected from the group consisting of O, N andS;and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6heteroatoms independently selected from the group consisting of O, N andS;Ring A can be illustrated but not limited to the following:

wherein

-   -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;        R^(III) represents optionally 1-3 substituents independently        selected from the group consisting of C₁-C₅ linear or branched        alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy,        hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen,        cyano, and nitro;        Z is selected from the group consisting of    -   (1′) (CH₂)_(i)N(R⁷)C(O)N(R⁸)(CH₂)_(j);    -   (2′) (CH₂)_(i)N(R⁷)C(S)N(R⁸)(CH₂)_(j);    -   (3′) (CH₂)_(i)N(R⁷)C(O);    -   (4′) C(O)N(R⁸)(CH₂)_(j);    -   (5′) (CH₂)_(i)N(R⁷)S(O)₂;    -   and (6′) S(O)₂N(R⁸)(CH₂)_(j);    -   wherein    -   i is 0 or 1;    -   j is 0 or 1;    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl.        Ring B is selected from the group consisting of:

(i′) Phenyl;(ii′) Naphthyl;(iii′) A 5 or 6 membered monocyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;and (iv′) An 8 to 10 membered bicyclic heteroaryl group which have 1-3heteroatoms independently selected from the group consisting of O, N andS;

Ring B can be illustrated but not limited to the following:

wherein

-   -   R¹ is independently selected from the group consisting of        hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl,        alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and        alkyl(NR²R³), wherein R² and R³ are independently selected from        the group consisting of hydrogen, alkyl, alkylcarbonyl,        alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,        and heterocyclylsulfonyl; alternatively R² and R³ and may be        taken together to form a 5-7 membered heterocyclic ring with N;    -   R^(IV) represents optionally 1-3 substituents, independently        selected from the group consisting

of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,nitro, and —NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; andincluding any pharmaceutically acceptable salt or prodrug.

Unless otherwise indicated, reference to a compound should be construedbroadly to include compounds, pharmaceutically acceptable salts,prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solidforms, crystal forms, polymorphic forms, hydrates, solvates,metabolites, mixtures of stereoisomers, mixtures of crystal forms,non-covalent complexes, and combinations thereof, of a chemical entityof a depicted structure or a chemical name. Whenever there is a conflictbetween chemical name and its structure drawing, the structure drawingshould be used to interpret the compound of the present invention.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A “prodrug” is a compound, which when administered to the body of asubject (such as a mammal), breaks down in the subject's metabolicpathway to provide an active compound of Formula I. More specifically, aprodrug is an active or inactive “masked” compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject or patient. One common formof a prodrug is a masked carboxylic acid group. Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bundgaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use. For example, conversion may occurby hydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion. Unless stereochemistry is explicitly andunambiguously depicted, a structure is intended to include everypossible stereoisomer, both pure or in any possible mixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be amorphous forms, crystal forms, polymorphs,and the mixtures thereof.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

2. USES, FORMULATION AND ADMINISTRATION

The present invention is also directed to the use of the compounds asprotein tyrosine kinase modulators and inhibitors. These compounds canbe used to treat diseases related to unregulated tyrosine kinase signaltransduction, for example, various cancers, blood vessel proliferativedisorders, fibrotic disorders, and neurodegenerative diseases. Inparticular, compounds of the present invention are useful for thetreatment and/or prevention of colorectal cancer, lung cancer,hematological cancer, renal cancer, liver cancer, breast cancer,diabetic retinopathy, macular degeneration, age-related maculardegeneration, retinopathy of prematurity, ocular angiogenesis, retinaledema, retinal ischemia, diabetic macular edema, cystoid macular edema,retinal vein occlusion, branch vein occlusion, preretinalneovascularization, laser-induced choroidal neovascularization,neovascularization associated with keratoplasty, glaucoma and oculartumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, diabetes mellitus, wound healing, transplant rejection,inflammation, neurodegenerative diseases and immune disorders in thehuman being.

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the diagnosis, cure, mitigation, treatment, or prevention ofdisease or other undesirable condition.

The present invention is also directed to the preparation of amedicament for the treatment and prevention of diseases and conditionsrelated with abnormal activities of tyrosine kinase receptors. Themedicament contains a pharmaceutical acceptable composition, whichcomprises the therapeutic effective amount of the compounds of presentinvention, together with a pharmaceutical acceptable carrier.

The pharmaceutical acceptable compositions contain therapeutic effectiveamount of the compounds of the present invention. These compositions canbe used as a medicament and administered to a mammal, such as a person,in need thereof. Different types of suitable dosage forms andmedicaments are well known in the art, and can be readily adapted fordelivery of the compounds of the present invention, such as, but notlimited to, systematic, parenteral, local and topical delivery. Thedosage forms can be tablets, capsules, intravenous injections,intramuscular injections, local injections, topical creams, gels andointments, eye drops, ophthalmic solutions, ophthalmic suspensions,ophthalmic emulsions, intravitreal injections, subtenon injections,ophthalmic biodrodible implant, and non-bioeordible ophthalmic insertsor depots, nasal sprays and ointment, various rectal or vaginalpreparations.

3. EXAMPLES

Some of the compounds of the present invention are listed in Table I.

TABLE 1 Exemplified Compounds of the Present Invention Example #Chemical Sructure MW Chemical Name 1

506 [({5-[4-(2-fluoro-5-{([2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl) amino]acetic acid 2

520 methyl[({5-[4-(2-fluoro-5- {[(2-fluro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]acetate 3

460 ({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)acetic acid 4

474 methyl({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyrdin-2-yl)-1H-pyrrol-3-yl] carbonyl}amino)acetate 5

402 5-[4-({3-[(3-methyl-2-furoyl)amino] pheny}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid 6

416 methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]- 1H-pyrrole-3-carboxylate 7

464 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylpheny)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy- 1H-pyrrole-3-carboxamide 8

533 4-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypiperidin-l-yl) carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide 9

505 N-(2,3-dihydroxypropyl)-5-[4- (3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrole-3- carboxamide 10

501 N-(2-fluoro-5-methylphenyl)-3-[(2- {4-[(3-hydroxypyrrolidin-l-yl)carbonyl]-1H-pyrrol-2-yl} pyridin-4-y}oxy]benzamide 11

446 5-[4-(3-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy- 1H-pyrrole-3-carboxamide 12

463 methyl 5-[4-(2-fluoro-5- {[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrole- 3-carboxylate 13

449 5-[4-(2-fluoro-5- {[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrole- 3-carboxylic acid 14

430 N-ethyl-5-(4-{3- [(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide 15

476 N-(2,3-dihydroxypropyl)-5- (4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxamide 16

402 5-(4-{3-[(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole- 3-carboxamide 17

418 N-hydroxy-5-(4-{3- [(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide 18

472 N-(3-{[2-(4-{[(3R)-3- hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl) pyridin-4-yl]oxy}phenyl)-3- methyl-2-furamide19

431 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]- 1H-pyrrole-3-carboxylic acid 20

445 methyl 5-[4-(3-{[(2-fluoro- 5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylate 21

477 2,3-dihydroxypropyl 5-(4- {3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxylate 22

413 5-[4-(3-{[(3-methylphenyl) amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole- 3-carboxylic acid 23

427 methyl 5-[4-(3-{[(3-methylphenyl) amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole- 3-carboxylate 24

464 2-hydroxyethyl 5-[4-(3- {[(3-methyl-2-thienyl)carbonyl]amino}phenoxy) pyridin-2-yl]-1H-pyrrole- 3-carboxylate 25

447 2-hydroxyethyl 5-(4-{3- [(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxylate 26

419 5-[4-(3-{[(3-methyl-2-thienyl) carbonyl]amino}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylic acid 27

433 methyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]- 1H-pyrrole-3-carboxylate 28

421 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylic acid 29

435 methyl 5-(4-{4-fluoro-3- [(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxylate 30

479 N-[dimethyl(oxido)- lambda~4~-sulfanylidene]-5-(4-{3-[(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide 31

472 N-(3-{[2-(4-{[(3S)-3- hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy} phenyl)-3-methyl-2-furamide 32

403 5-(4-{3-[(3-methyl-2-furoyl)amino] phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid 33

417 methyl 5-(4-{3-[(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate 34

359 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide 35

417 methyl 4-(4-{3-{[(3-methyl-2-furoyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate 36

387 2-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide 37

359 3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide 38

573 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3- carboxamide 39

479 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-hydroxy-1H-pyrrole-3-carboxamide 40

521 {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetic acid 41

535 methyl {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate 42

478 methyl 4-{4-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl} thiophene-2-carboxylate 43

603 (4S)-5-(ethylamino)-4- {[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl] amino}-5-oxopentanoic acid 44

659 tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl) amino]carbonyl]amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl] amino}-5-oxopentanoate 45

632 (2S)-5-tert-butoxy-2- {[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl})-1H-pyrrol-3-yl)carbonyl]amino}-5- oxopentanoic acid 46

646 5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}pentanedioate 47

664 bis(2-hydroxyethyl)-2-{[(5-{4- [3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate 48

518 3-{[(5-{4-[3-fluoro-4-({[(3-methyphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl}amino}propanoic acid 49

576 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid 50

615 methyl 1-(3-{[(5-{4-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2- carboxylate 51

573 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{2- [(3S)-3-hydorxypyrrolidin-1-yl]-2-oxoethyl}-1H-pyrrole-3-carboxamide 52

619 N-{4-[(2,3-dihydroxypropyl) (methyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide 53

615 5-{4-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypiperidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide 54

605 N-{4-[(2,3-dihydroxypropyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3- carboxamide 55

531 N-(4-amino-4-oxobutyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide 56

577 N-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxamide 57

664 5-(2,3-dihydroxypropyl)1-methyl 2- {[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino} pentanedioate 58

724 bis(2,3-dihydroxypropyl)2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl] amino}pentanedioate 59

590 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-methoxy-5- oxopentanoic acid 60

559 N-[4-(ethylamino)-4-oxobutyl]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 61

601 5-{4-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3- hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide 62

547 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-[4-(hydroxyamino)-4-oxobutyl]-1H-pyrrole-3-carboxamide 63

576 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid 64

604 dimethyl 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate 65

562 1-[(5-{4-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylic acid 66

550 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl) carbonyl]amino}butanoic acid 67

578 ethyl 4-{[5-{4-[3-fluoro-4-({[2- fluoro-5-methyphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanote 68

532 4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl) carbonyl]amino}butanoic acid 69

536 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoic acid 70

474 N-ethyl-5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxamide 71

503 {[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid 72

518 methyl {[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino} acetate 73

516 1-(2-fluoro-4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl))-3-(3-methylphenyl)urea 74

530 1-{2-fluoro-4-(2-{4-[(3-hydroxypiperidin-1yl)carbonyl]-1H-2-yl}pyridin-4-yl)oxy]phenyl}- 3-(3-methylphenyl)urea75

446 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid 76

460 methyl 5-{4-[3-fluoro({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylate 77

622 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-1H-pyrrole-3- carboxamide 78

532 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid 79

560 ethyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate 80

463 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio} pyridin-2-yl)-1H-pyrrole-3-carboxylic acid81

518 3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoic acid 82

576 4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoic acid 83

544 1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3- carboxylic acid 84

503 {[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid 85

518 methyl {[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate 86

594 1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidine- 4-sulfonic acid 87

590 methyl 4-{S-methyl-N-[(5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl-)carbonyl]sulfonimidoyl}butanoate 88

477 methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio} pyridin-2-yl)-1H-pyrrole-3-carboxylate89

441 N-methyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 90

512 1-{4-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl}-1H-pyrrol-2-yl}pyridin-4-yl)oxy] phenyl}-3-(3-methylphenyl)urea 91

498 1-{4-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3-(3-methylphenyl)urea 92

502 N-(2,3-dihydroxypropyl)-5-{4-[4- ({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 93

456 N-ethyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 94

427 5-{4-[4-({[(3-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide 95

443 N-hydroxy-5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxamide 96

464 5-{4-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylic acid97

504 N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-{4-[4-({[(3-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole- 3-carboxamide 98

561 2-hydroxyethyl 5-(4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl) amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate 99

592 5-(4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-N-[dimethyl(oxido)-lambda~4~-sulfanylidene]- 1H-pyrrole-3-carboxamide100

608 methyl 4-{N-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]-S-methylsulfonimidoyl}butanoate 101

522 N-[dimethyl(oxido)-lambda~ 4~-sulfanylidene]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide 102

601 methyl (2S)-1-(2-{[(5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl) pyrrolidine-2-carboxylate 103

502 N,N-diethyl-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide 104

529 1-(2-fluoro-5-methylphenyl)-3- {4-[(2-{4-[(4-methypiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl) oxy]phenyl}urea 105

543 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl]amino)phenoxy]pyridin-2-yl}- N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide 106

471 1-[4-({2-[4-(aziridin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy) phenyl]-3-(2-fluoro-5-methylphenyl)urea107

445 5-{4-[4-({[(2-fuoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 108

461 5-{4-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}- N-hydroxy-1H-pyrrole-3-carboxamide 109

486 1-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3- (2-fluoro-5-methylphenyl)urea110

504 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide 111

549 2-(2-methoxyethoxy)ethyl 5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate 112

474 N-ethyl-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 113

505 2-methoxyethyl 5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate 114

504 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-methoxyethyl)- 1H-pyrrole-3-carboxamide 115

428 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid 116

442 methyl 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate 117

464 5-{4-[2-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid 118

478 methyl 5-{4-[2-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}1H--pyrrole-3-carboxylate 119

500 5-(4-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid 120

514 methyl 5-(4-{4-[({[4-fluoro- 3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy} pyridin-2-yl)-1H-pyrrole-3-carboxylate 121

517 5-(4-{4-[({[4-chloro-3- (trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin- 2-yl)-1H-pyrrole-3-carboxylic acid122

531 methyl 5-(4-{4-[({[4-chloro-3- (trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin- 2-yl)-1H-pyrrole-3-carboxylate 123

463 4-{4-[4-({[((2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid 124

490 2-hydroxyethyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}1H-pyrrole-2-carboxylate 125

572 {l-[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl]amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl) carbonyl]piperidin-4-yl}aceticacid 126

586 methyl {l-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin- 4-yl}acetate 127

520 N-(2,3-dihydroxypropyl)-5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide 128

490 5-{4-{4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2- hydroxyethyl)-1H-pyrrole-3-carboxamide129

530 1-(2-fluoro-5-methylphenyl)- 3-{4-[(2-{4-[(4-hydroxypiperidin-l-yl)carbonyl]-1H-pyrrol-2-yl}pyridin- 4-yl)oxy]phenyl}urea 130

521 2,3-dihydroxypropyl 5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylate 131

490 2-hydroxyethyl 5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl)amino)phenoxy] pyridin-2-yl}-1H-pyrrole-3-carboxylate 132

516 1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl] oxy}phenyl)urea 133

516 1-(2-fluoro-5-methylphenyl)-3- (4-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin- 4-yl]oxy}phenyl)urea 134

446 5-{4-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid 135

460 methyl 5-{4-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate 136

460 methyl 4-{4-[3-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl} 1H-pyrrole-2-carboxylate 137

522 N-[dimethyl(oxido)-lambda~ 4~-sulfanylidene]-4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide 138

474 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N,N-dimethyl-1H-pyrrole-2-carboxamide 139

459 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- N-methyl-1H-pyrrole-2-carboxamide140

576 1-tert-butyl 2-methyl 4-{6-amino-4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-1,2-dicarboxylate 141

417 1-(4-{[2-amino-6-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-(2-fluoro- 5-methylphenyl)urea 142

446 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino] acidcarbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrole-2- carboxylic acid 143

460 methyl 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrole-2-carboxylate 144

402 1-(2-fluoro-5-methylphenyl)-3-(4- {[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea 145

354 1-phenyl-3-{4-[6-(1H-pyrrol-2-yl) pyridin-3-yl]pheny}urea 146

386 1-(2-fluoro-5-methylphenyl)- 3-{3-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea 147

386 1-(2-fluoro-5-methylphenyl)-3- {4-[2-(1H-pyrrol-3-yl)pyridin-4-yl]phenyl}urea 148

386 1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl} urea

3.1 Compound Synthesis and Characterization Preparation of methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate

To a mixture of methyl-1H-pyrrole-3-carboxylate (5.0 g, 39.9 mmol),bis(pinacolato)diboron (5.37 g, 21.1 mmol),4,4′-di-tert-butyl-2,2′-bipyridine (0.054 g, 0.20 mmol) and[Ir(OMe)(COD)]₂ (0.067 g, 0.099 mmol) was added cyclohexane (60 mL). Themixture stirred at 90° C. for 5 hours. The mixture was cooled to roomtemperature and filtered, washing with ample amounts of water and twicewith hexanes. The light orange solid was collected and dried in a vacuumoven at 55° C. to afford methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(6.99 g, 70% yield).

Preparation of 3-(2-Bromo-pyridin-4-yloxy)-benzoic acid

A mixture of 2-bromo-4-chloro-pyridine (200 mg, 1.04 mmol),methyl-3-hydroxybenzoate (158 mg, 1.04 mmol), cesium carbonate (507 mg,1.56 mmol) in 10 ml of anhydrous DMSO was heated at 66° C. for 5 hours.The mixture was diluted with ethyl acetate (100 ml), washed with brine(3×50 ml), dried over Na₂SO₄ and evaporated to give a colorless oil. Theoil was dissolved in MeOH (8 ml), and 2M NaOH solution (4 ml, 8 mmol)was added. The mixture was heated at 60° C. for 20 minutes, poured into50 ml of water, and acidified to pH=4. The precipitates were filtered,washed with water and dried in vacuo to give3-(2-bromo-pyridin-4-yloxy)-benzoic acid as white solid. Yield: 170 mg,56%. ¹H NMR (DMSO-d₆) δ: 13.24 (br. s., 1H), 8.27 (d, J=5.9 Hz, 1H),7.87 (d, J=7.6 Hz, 1H), 7.58-7.68 (m, 2H), 7.45-7.52 (m, 1H), 7.19 (d,J=2.1 Hz, 1H), 7.00 (dd, J=5.7, 2.2 Hz, 1H)

LR MS (ES−): 292 (M−H), 294

Preparation of 3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide

A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (170 mg, 0.58mmol), HATU (265 mg, 0.69 mmol),) m-toluidine (93 mg, 0.87 mmol) andN,N-diisopropylethylamine (164 mg, 1.28 mmol) in anhydrous DMF (10 ml)was stirred at room temperature for 20 minutes. The mixture was pouredinto 100 ml of water. The precipitates were filtered, washed with waterand dried in vacuo to give3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide as off-white solid.Yield: 150 mg, 68%.

¹H NMR (DMSO-d₆) δ: 10.18 (s, 1H), 8.29 (d, J=5.9 Hz, 1H), 7.91 (d,J=7.6 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.50-7.60 (m, 2H),7.45 (dd, J=7.9, 1.8 Hz, 1H), 7.16-7.25 (m, 2H), 7.02 (dd, J=5.7, 2.2Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 2.29 (s, 3H)

LR MS (ES+): 405 (M+Na⁺), 407

LR MS (ES−): 381 (M−H), 383

Preparation of3-(2-Bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide

A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (200 mg, 0.68mmol), HATU (312 mg, 0.82 mmol),) 2-fluoro-5-methylaniline (125 mg, 1.0mmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol) in anhydrous DMF(10 ml) was stirred at 60° C. for 90 minutes. The mixture was pouredinto 100 ml of water. The precipitates were filtered, washed with waterand dried in vacuo to give3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide asoff-white solid. Yield: 200 mg, 74%.

Example 1[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]aceticacid

To a stirred solution of methyl[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate(110 mg, 0.21 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded IM NaOH solution (1 ml, 1 mmol). The mixture was stirred at roomtemperature for 1 hour, and poured into 100 ml of water. 2M HCl wasadded until pH=4. The precipitates were filtered, washed with water anddried in vacuo to give[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]aceticacid as white solid. Yield: 100 mg, 93%.

¹H NMR (DMSO-d₆) δ: 12.41 (br. s., 1H), 11.87 (br. s., 1H), 10.12 (s,1H), 8.42 (d, J=5.6 Hz, 1H), 8.19 (t, J=6.0 Hz, 1H), 7.95-8.04 (m, 2H),7.63 (dd, J=10.1, 8.7 Hz, 1H), 7.41 (dd, J=3.1, 1.6 Hz, 1H), 7.35 (dd,J=7.3, 1.8 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 7.09-7.18 (m, 2H), 7.04 (td,J=5.3, 2.3 Hz, 1H), 6.81 (dd, J=5.9, 2.3 Hz, 1H), 3.82 (d, J=5.9 Hz,2H), 2.27 (s, 3H)

LR MS (ES−): 505 (M−H)

Example 2 methyl[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate

Similar procedure as Example 1.

¹H NMR (DMSO-d₆) δ: 11.95 (br. s., 1H), 10.12 (s, 1H), 8.44 (d, J=5.9Hz, 1H), 8.33 (t, J=5.9 Hz, 1H), 7.97-8.03 (m, 2H), 7.61-7.67 (m, 1H),7.45 (br. s., 1H), 7.33-7.37 (m, 1H), 7.30 (s, 1H), 7.18 (br. s., 1H),7.14 (dd, J=10.3, 8.5 Hz, 1H), 7.02-7.08 (m, 1H), 6.86 (br. s., 1H),3.91 (d, J=5.9 Hz, 2H), 3.61 (s, 3H), 2.27 (s, 3H)

LR MS (ES+): 521 (MH), 543 (M+Na⁺)

LR MS (ES−): 519 (M−H)

Preparation of 4-(3-Aminophenoxy)-2-chloropyridine

To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) wasadded Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutesand then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixturewas stirred at 120° C. for 1.5 h. The mixture was cooled and dilutedwith water. The aqueous solution was extracted with EtOAc (3×100 mL).The organic extracts were combined, dried over MgSO4 and concentrated toafford a dark oil. The oil was purified via column chromatography,eluting with 30-40% EtOAc/hexanes, to afford4-(3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid.

Preparation of methyl5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of 4-(3-aminophenoxy)-2-chloropyridine (4.0 g, 18.13 mmol),methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(6.82 g, 27.16 mmol) and Pd(PPh3)₄ (4.20 g, 3.63 mmol) was added to athick walled reaction vessel and purged with N2. A solution of 2M K2CO3(13.59 mL) was added, followed by DME (70 mL). The reaction vessel wassealed and the mixture stirred at 92° C. for 18 h. The reaction vesselwas cooled to room temperature and the mixture was filtered over celite,washing with EtOAc. The filtrate was concentrated and the resultant darkoil was purified via column chromatography, eluting with 40-80%EtOAc/hexanes to afford methyl5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (2.85 g, 51%yield).

Example 3({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)aceticacid

Similar procedure as Example 1.

¹H NMR (DMSO-d₆) δ: 12.42 (br. s., 1H), 11.91 (br. s., 1H), 10.20 (s,1H), 8.41 (d, J=5.6 Hz, 1H), 8.21 (t, J=5.4 Hz, 1H), 7.76 (s, 1H),7.65-7.73 (m, 2H), 7.36-7.47 (m, 2H), 7.26 (br. s., 1H), 7.12 (br. s.,1H), 6.86-6.98 (m, 1H), 6.77 (br. s., 1H), 6.56 (s, 1H), 3.81 (d, J=5.9Hz, 2H), 2.29 (s, 3H)

LR MS (ES−): 459 (M−H)

Example 4methyl({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetate

Similar procedure as Example 3.

¹H NMR (DMSO-d₆) δ: 11.88 (br. s., 1H), 10.19 (s, 1H), 8.40 (d, J=5.6Hz, 1H), 8.32 (t, J=5.6 Hz, 1H), 7.76 (s, 1H), 7.65-7.72 (m, 2H),7.36-7.44 (m, 2H), 7.23 (d, J=2.1 Hz, 1H), 7.08 (br. s., 1H), 6.90 (d,J=7.3 Hz, 1H), 6.75 (dd, J=5.6, 1.8 Hz, 1H), 6.56 (s, 1H), 3.89 (d,J=5.6 Hz, 2H), 3.60 (s, 3H), 2.29 (s, 3H)

LR MS (ES+): 475 (MH), 497 (M+Na⁺)

LR MS (ES−): 473 (M−H)

Preparation of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine

To a degassed (15 min, N₂) suspension of 2-chloro-4-iodopyridine (3.0 g,12.53 mmol), 3-nitroaniline (1.82 g, 13.18 mmol), BINAP (0.39 g, 0.626mmol) and Cs₂CO₃ (8.16 g, 25.04 mmol) in toluene (72 mL) was addedPd(OAc)₂ (0.084 g, 0.374 mmol). The reaction tube was sealed and themixture stirred at 90° C. for 18 h. The mixture was cooled to rt andfiltered, washing with EtOAc. The orange/yellow solid collected waswashed with CH₂Cl₂ until all the product washed through into thefiltrate. The filtrate was concentrated to afford2-Chloro-N-(3-nitrophenyl)pyridine-4-amine as a bright yellow solid.Additional product was collected from the solid collected uponconcentration of the previous filtrate, after washing with CH₂Cl₂. Nofurther purification. Total amount of product collected was 2.85 g (91%yield).

Preparation of tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate

To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine(2.70 g, 10.82 mmol) in THF (45 mL) was added Et₃N (6.32 mL, 45.3 mmol).The mixture was cooled to 0° C., and DMAP (0.0135 g, 0.110 mmol) andBOC₂O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt andstirred for 18 h. The mixture was quenched with ice and diluted withwater. Extracted with EtOAc (3×200 mL), washed with brine and water,dried (MgSO₄), and concentrated. A dark oil was afforded, which waspassed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes.Concentrated and dried under high vacuum to afford tert-Butyl2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield).

Preparation of methyl5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate

A mixture of tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate(3.65 g, 10.43 mmol),methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(5.48 g, 21.82 mmol), xantphos (0.72 g, 1.25 mmol) and Pd₂dba₃ (0.72 g,0.79 mmol) was added to a thick walled reaction vessel and purged withN₂. A solution of 2M K₂CO₃ (8.76 mL) was added, followed by dioxane (67mL). The reaction vessel was sealed and the mixture stirred at 105° C.for 18 h. The reaction vessel was cooled to rt and the mixture wasfiltered over celite, washing with EtOAc. The filtrate was concentratedto afford a dark oil, which was purified via column chromatographyeluting with 30-50% EtOAc/hexanes to afford methyl5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate(2.98 g, 65% yield) as an orange oil.

Preparation of methyl5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate

Methyl5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate(0.40 g, 0.91 mmol) was taken up in toluene (38 mL) and SiO₂ (9.0 g) wasadded. The mixture stirred at reflux for 20 h. The mixture was cooled tort and filtered over celite, washing with EtOAc. The filtrate wasconcentrated to a bright orange color. The solid was taken up in hexanesand filtered. The solid was then washed with CH₂Cl₂/hexanes to affordmethyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate(0.15 g, 49% yield) as a bright yellow solid.

Preparation of methyl5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate

Methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate(1.32 g, 3.9 mmol) was taken up in EtOAc/EtOH (1:1; 90 mL) and purgedwith N₂. Pd/C (10%, 0.145 g) was added and the mixture was stirred underan atmosphere of H₂ at rt for 18 h. The mixture was filtered overcelite, washing with EtOAc/EtOH. The filtrate was concentrated, takenback up in EtOAc and filtered over celite again to remove any residualcatalyst. The filtrate was concentrated again and taken back up inEtOAc. The solution was filtered and the filtrate was concentrated toafford a tan solid. The solid was washed with CH₂Cl₂/hexanes (1:2) anddried under high vacuum to afford methyl5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.15g, 96% yield) as a tan solid.

Example 55-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid

To a stirred solution of methyl5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate(10 mg, 0.024 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded 2 ml of IM NaOH (2 mmol) solution. The mixture was heated in a 60°C. bath for 16 hours, cooled to room temperature and poured into 100 mlof water. 2M HCl was added until pH=5. The resulting precipitates werefiltered, washed with water, and dried in vacuo to give5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid as light brown solid. Yield: 2 mg.

Example 6 methyl5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of 3-methyl-2-furoic acid (22 mg, 0.18 mmol), HATU (73 mg,0.19 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in anhydrousDMF (10 ml) was stirred at room temperature for 10 minutes, followed byaddition of methyl5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (50mg, 0.16 mmol). The mixture was stirred at room temperature for 3 hoursand poured into 100 ml of water. The precipitates were filtered, washedwith water and dried in vacuo to give methyl5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylateas off-white solid. Yield: 10 mg, 15%.

¹H NMR (DMSO-d₆) δ: 13.60 (br. s., 1H), 12.37 (br. s., 1H), 10.14 (s,1H), 8.15 (d, J=6.5 Hz, 1H), 7.86 (t, J=1.9 Hz, 1H), 7.77 (d, J=1.8 Hz,1H), 7.58 (br. s., 1H), 7.52 (d, J=7.6 Hz, 1H), 7.32-7.38 (m, 2H), 7.22(br. s., 1H), 6.97 (d, J=7.6 Hz, 1H), 6.86 (dd, J=6.2, 2.1 Hz, 1H), 6.57(d, J=1.8 Hz, 1H), 3.71 (s, 3H), 2.32 (s, 3H)

LR MS (ES+): 417 (MH)

LR MS (ES−): 415 (M−H)

Example 75-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 1.

¹H NMR (DMSO-d₆) δ: 11.85 (br. s., 1H), 10.56 (br. s., 1H), 10.12 (s,1H), 8.66 (br. s., 1H), 8.41 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.3 Hz, 2H),7.63 (t, J=9.4 Hz, 1H), 7.30-7.40 (m, 2H), 7.27 (br. s., 1H), 7.10-7.18(m, 1H), 7.01-7.10 (m, 2H), 6.75-6.85 (m, 1H), 2.26 (s, 3H)

LR MS (ES+): 487 (M+Na⁺)

LR MS (ES−): 463 (M−H)

Example 84-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide

Similar procedure as Example 1.

LR MS (ES+): 533 (MH), 555 (M+Na⁺)

LR MS (ES−): 531 (M−H)

Example 9N-(2,3-dihydroxypropyl)-5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 1.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 10.11 (s, 1H), 8.41 (d, J=5.6Hz, 1H), 7.89 (d, J=7.0 Hz, 1H), 7.83 (t, J=5.6 Hz, 1H), 7.77 (s, 1H),7.63 (t, J=7.9 Hz, 1H), 7.42-7.46 (m, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.35(d, J=7.3 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 7.09-7.16 (m, 2H), 7.02-7.06(m, 1H), 6.76 (dd, J=5.7, 2.5 Hz, 1H), 4.77 (d, J=5.0 Hz, 1H), 4.53 (t,J=6.0 Hz, 1H), 3.50-3.56 (m, 1H), 3.25-3.30 (m, 3H), 3.08-3.14 (m, 1H),2.27 (s, 3H)

LR MS (ES+): 505 (MH), 527 (M+Na⁺)

LR MS (ES−): 503 (M−H)

Example 10N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide

A mixture of5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid (50 mg, 0.12 mmol), HATU (55 mg, 0.14 mmol) andN,N-diisopropylethylamine (34 mg, 0.26 mmol) in anhydrous DMF (8 ml) wasstirred at room temperature for 10 minutes, followed by addition of(S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred foranother 10 minutes and poured into 100 ml of water. The precipitateswere filtered, washed with water and dried in vacuo to giveN-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamideas white solid. Yield: 40 mg, 69%.

¹H NMR (DMSO-d₆) δ: 11.91 (br. s., 1H), 10.12 (s, 1H), 8.42 (d, J=5.6Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.76 (s, 1H), 7.63 (t, J=7.9 Hz, 1H),7.32-7.51 (m, 3H), 7.26 (d, J=6.7 Hz, 1H), 6.99-7.20 (m, 3H), 6.73 (dd,1H), 4.91 (br. s., 1H), 4.30 (br. s., 1H), 3.76 (br. s., 2H), 3.50 (br.s., 2H), 2.28 (s, 3H), 1.86 (br. s., 2H)

LR MS (ES+): 501 (MH), 523 (M+Na⁺)

LR MS (ES−): 499 (M−H)

Example 115-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 10.

¹H NMR (DMSO-d₆) δ: 11.84 (br. s., 1H), 10.56 (br. s., 1H), 10.10 (s,1H), 8.65 (br. s., 1H), 8.40 (d, J=5.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H),7.76 (br. s., 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (dd, J=7.9, 1.5 Hz, 1H),7.35 (d, J=6.7 Hz, 1H), 7.31 (br. s., 1H), 7.25 (d, J=1.8 Hz, 1H), 7.13(dd, J=10.3, 8.5 Hz, 1H), 7.01-7.07 (m, 2H), 6.75 (dd, J=5.7, 2.2 Hz,1H), 2.27 (s, 3H)

LR MS (ES+): 469 (M+Na⁺)

LR MS (ES−): 445 (M−H)

Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methylester

4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) wasdissolved in dimethylformamide (9 mL) under nitrogen at roomtemperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) wasadded in portions over 30 min. The reaction was stirred for 90 minutesand then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0mmol) was added in small portions over 50 min. The reaction was stirredat room temperature for 17.5 h. Water (200 ml) was added and the mixturestirred until a brown lump formed. The water was decanted and theresidue dissolved in EtOAc (150 mL). The solution was washed with brine,dried (MgSO₄), filtered and evaporated to give3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield:3.10 g.

Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid

3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester (2.81 g,10.0 mmol) was dissolved in tetrahydrofuran (15 mL) and mixed with 2Mlithium hydroxide (15 mL, 30 mmol). The suspension was stirred for 5 h.To the reaction was added water, then extracted with EtOAc. The aqueouslayer was treated with 6M HCl (5 mL, 30 mmol) and then extracted withEtOAc (3×25 mL). The extract was dried (MgSO₄), filtered and evaporatedto 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid. Yield: 2.22 g, 83%.

Preparation of3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide

A solution of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid (2.22 g,8.29 mmol), 2-fluoro-5-methylaniline (1.56 g, 12.4 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 3.78 g, 9.95 mmol) and N-methylmorpholine(2.00 mL, 18.2 mmol) in dimethylformamide (22 mL) was heated at 90° C.for 2 h. The solvent was evaporated in vacuo at 50° C. To the residuewas added water resulting in a thick oil. The water was decanted and theoil dissolved in EtOAc then extracted twice with water, IM hydrochloricacid and brine. The organic layer was dried (MgSO₄), filtered andevaporated to crude 6 (3.37 g). Trituration with dichloromethane (25 mL)gave3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamideas white solid. Yield: 1.788 g, 58%.

Example 12 methyl5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide(1.217 g, 3.25 mmol), methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(1.63 g, 6.50 mmol) and potassium carbonate (0.67 g, 4.87 mmol) in water(2.5 mL) and dioxane (15 mL) was purged with nitrogen for severalminutes. To the mixture was added tetrakis-triphenylphosphinepalladium(0) (0.18 g, (0.16 mmol). The reaction was sealed undernitrogen and heated at 100° C. for 15 h. The cooled reaction was mixedwith dichloromethane and filtered through Celite. The red solution wasevaporated. The resulting oil was dissolved in dichloromethane, put on acolumn of silica gel (80 g) and eluted with hexane/EtOAc (1:1) to affordmethyl5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylateas white solid. Yield: 1.162 g, 77%.

Example 135-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 12.

¹H NMR (DMSO-d₆) δ: 12.03 (br. s., 1H), 11.85 (br. s., 1H), 10.11 (s,1H), 8.42 (d, J=5.6 Hz, 1H), 7.98 (d, J=6.2 Hz, 2H), 7.62 (t, J=9.4 Hz,1H), 7.43 (br. s., 1H), 7.30-7.39 (m, 2H), 7.08-7.19 (m, 2H), 7.04 (br.s., 1H), 6.79 (d, J=3.2 Hz, 1H), 2.26 (s, 3H)

LR MS (ES−): 448 (M−H)

Example 14N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31.

LR MS (ES+): 453 (M+Na⁺)

Example 15N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31.

¹H NMR (DMSO-d₆) δ:11.83 (br. s., 1H), 10.21 (s, 1H), 8.40 (d, J=5.9 Hz,1H), 7.85 (t, J=6.0 Hz, 1H), 7.78 (s, 1H), 7.63-7.74 (m, 2H), 7.35-7.48(m, 2H), 7.23 (d, J=2.1 Hz, 1H), 7.10 (s, 1H), 6.85-6.96 (m, 1H), 6.75(dd, J=5.7, 2.2 Hz, 1H), 6.57 (s, 1H), 4.78 (d, J=4.7 Hz, 1H), 4.53 (t,J=5.9 Hz, 1H), 3.48-3.61 (m, 1H), 3.24-3.33 (m, 3H), 3.04-3.19 (m, 1H),2.30 (s, 3H)

LR MS (ES+): 499 (M+Na⁺)

LR MS (ES−): 475 (M−H)

Example 165-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 10.21 (s, 1H), 8.40 (d, J=5.9Hz, 1H), 7.77 (s, 1H), 7.65-7.74 (m, 2H), 7.31-7.48 (m, 3H), 7.23 (d,J=1.2 Hz, 1H), 7.07 (br. s., 1H), 6.86-6.95 (m, 1H), 6.75 (d, J=3.5 Hz,2H), 6.57 (s, 1H), 2.30 (s, 3H)

LR MS (ES−): 401 (M−H)

Example 17N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31.

¹H NMR (DMSO-d₆) δ:11.84 (br. s., 1H), 10.49-10.64 (m, 1H), 10.20 (s,1H), 8.60-8.74 (m, 1H), 8.39 (d, J=5.9 Hz, 1H), 7.65-7.81 (m, 3H), 7.41(t, J=7.9 Hz, 1H), 7.32 (br. s., 1H), 7.23 (s, 1H), 7.02 (br. s., 1H),6.85-6.94 (m, 1H), 6.69-6.78 (m, 1H), 6.57 (s, 1H), 2.30 (s, 3H)

LR MS (ES−): 417 (M−H)

Example 18N-(3-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide

Similar procedure as Example 31.

¹H NMR (DMSO-d₆) δ: 11.90 (br. s., 1H), 10.20 (s, 1H), 8.40 (d, J=5.6Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.64-7.73 (m, 2H), 7.36-7.46 (m, 2H),7.21-7.30 (m, 1H), 7.03-7.13 (m, 1H), 6.85-6.93 (m, 1H), 6.70 (dd,J=5.7, 2.2 Hz, 1H), 6.57 (d, J=1.5 Hz, 1H), 4.90 (br. s., 1H), 4.30 (m,1H), 3.76 (m, 1H), 3.49 (m, 2H), 2.30 (s, 3H), 1.86 (m, 2H)

LR MS (ES−): 471 (M−H)

Example 195-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

To a stirred solution of5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid methyl ester (140 mg, 0.31 mmol) in THF (8 ml) was added 5M NaOHsolution (1 ml, 5 mmol). The mixture was heated at 70° C. for 3 hours,cooled to room temp, and poured into 100 ml of water. 2M HCl was addeduntil pH=4. The precipitates were filtered, washed with water, and driedto give5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid as white solid. Yield: 120 mg, 92%.

¹H NMR (d₆-DMSO): 12.03 (br. s., 1H), 11.89 (br. s., 1H), 10.11 (s, 1H),8.42 (d, J=5.6 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.77 (s, 1H), 7.56-7.71(m, 1H), 7.30-7.54 (m, 4H), 6.97-7.23 (m, 3H), 6.75 (dd, J=5.6, 2.1 Hz,1H), 2.28 (s, 3H)

LR MS (ES+): 454 (M+Na⁺)

LR MS (ES−): 430 (M−H)

Example 205-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid methyl ester

A mixture of3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide (200mg, 0.50 mmol),methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(251 mg, 1.0 mmol) and PdCl₂(dppf).CH₂Cl₂ (10 mg, 0.012 mmol) was addedto a thick-walled reaction vessel and purged with N₂. A solution of 2MNa₂CO₃ (0.5 mL) was added, followed by DMSO (8 mL). The reaction vesselwas sealed and the mixture stirred at 95° C. for 16 h. The reactionvessel was cooled to room temperature and the mixture was poured into100 ml of water. The precipitates were filtered, washed with water anddried to give the crude, which was purified via column chromatographyeluting with 30-40% EtOAc/hexanes to afford5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid methyl ester (150 mg, 58% yield).

¹H NMR (d₆-DMSO): 12.14 (br. s., 1H), 10.11 (s, 1H), 8.43 (d, J=5.6 Hz,1H), 7.89 (d, J=7.9 Hz, 1H), 7.77 (s, 1H), 7.64 (t, J=7.9 Hz, 1H),7.41-7.50 (m, 3H), 7.35 (s, 1H), 7.09-7.21 (m, 2H), 7.06 (dd, J=5.1, 1.9Hz, 1H), 6.76 (dd, J=5.6, 2.3 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 3H)

LR MS (ES+): 468 (M+Na⁺)

LR MS (ES−): 444 (M−H)

Example 21

Similar procedure as Example 25.

2,3-dihydroxypropyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

Example 225-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 19.

¹H NMR (DMSO-d₆) δ: 12.03 (br. s., 1H), 11.86 (br. s., 1H), 10.19 (s,1H), 8.42 (d, J=5.6 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.78 (s, 1H),7.50-7.69 (m, 3H), 7.32-7.46 (m, 3H), 7.21 (t, J=7.8 Hz, 1H), 7.06 (s,1H), 6.91 (d, J=7.3 Hz, 1H), 6.74 (dd, J=5.6, 2.3 Hz, 1H), 2.28 (s, 3H)

Example 235-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylicacid methyl ester

Similar procedure as Example 20.

¹H NMR (DMSO-d₆) δ:12.14 (br. s., 1H), 10.18 (s, 1H), 8.43 (d, J=5.6 Hz,1H), 7.89 (d, J=7.9 Hz, 1H), 7.78 (s, 1H), 7.50-7.68 (m, 3H), 7.38-7.48(m, 3H), 7.21 (t, J=7.8 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J=7.6 Hz, 1H),6.75 (dd, J=5.7, 2.2 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 3H)

LR MS (ES+): 450 (M+Na⁺)

LR MS (ES−): 426 (M−H)

Example 24 2-hydroxyethyl5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

Similar procedure as Example 25.

¹H NMR (d₆-DMSO): 12.13 (br. s., 1H), 10.13 (s, 1H), 8.43 (d, J=5.9 Hz,1H), 7.68 (d, J=5.0 Hz, 1H), 7.56-7.64 (m, 2H), 7.40-7.52 (m, 3H), 7.14(s, 1H), 7.03 (d, J=5.0 Hz, 1H), 6.89-6.98 (m, 1H), 6.76 (dd, J=5.7, 2.2Hz, 1H), 4.83 (t, J=5.9 Hz, 1H), 4.15 (t, J=5.1 Hz, 2H), 3.64 (q, J=5.6Hz, 2H), 2.44 (s, 3H)

LR MS (ES+): 486 (M+Na⁺)

LR MS (ES−): 462 (M−H)

Example 25 2-hydroxyethyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

A mixture of5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid (70 mg, 0.17 mmol), ethylene glycol (1 ml),1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl,40 mg, 0.21 mmol) and 4-dimethylaminopyridine (DMAP, 10 mg, 0.08 mmol)in anhydrous DMF (10 ml) was stirred at 70° C. for 3 hours then roomtemperature for 16 hours. The mixture was poured into 100 ml of water.Saturated NaHCO₃ solution was added until pH=9. The precipitates werefiltered, washed with water and dried in vacuo to give the crude, whichwas purified by silica gel chromatography eluting with a gradient of3-4% MeOH/CHCl₃ to give 2-hydroxyethyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylateas white solid.

Yield: 40 mg, 51%.

¹H NMR (d₆-DMSO): 12.13 (br. s., 1H), 10.22 (s, 1H), 8.43 (d, J=5.9 Hz,1H), 7.79 (s, 1H), 7.70 (s, 2H), 7.36-7.54 (m, 3H), 7.13 (br. s., 1H),6.86-6.97 (m, 1H), 6.72-6.80 (m, 1H), 6.59 (s, 1H), 5.75 (s, 1H), 4.83(t, J=5.3 Hz, 1H), 4.14 (t, J=4.7 Hz, 2H), 3.58-3.69 (m, 2H), 2.32 (s,3H)

LR MS (ES+): 470 (M+Na⁺)

LR MS (ES−): 446 (M−H)

Example 265-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 32.

¹H NMR (d₆-DMSO): 12.04 (br. s., 1H), 11.87 (s, 1H), 10.13 (s, 1H), 8.42(d, J=6.2 Hz, 1H), 7.68 (d, J=4.7 Hz, 1H), 7.57-7.64 (m, 2H), 7.40-7.49(m, 2H), 7.38 (dd, J=3.2, 1.5 Hz, 1H), 7.05-7.09 (m, 1H), 7.03 (d, J=5.0Hz, 1H), 6.90-6.97 (m, 1H), 6.75 (dd, J=5.7, 2.5 Hz, 1H), 2.44 (s, 3H)

LR MS (ES+): 442 (M+Na⁺)

LR MS (ES−): 418 (M−H)

Example 27 methyl5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

Similar procedure as Example 33.

¹H NMR (DMSO-d₆) δ: 12.12 (br. s., 1H), 10.10 (s, 1H), 8.35-8.45 (m,1H), 7.65 (d, J=5.0 Hz, 1H), 7.55-7.60 (m, 2H), 7.37-7.45 (m, 3H), 7.10(s, 1H), 7.00 (d, J=5.0 Hz, 1H), 6.87-6.93 (m, 1H), 6.73 (dd, J=5.6, 2.3Hz, 1H), 3.69 (s, 3H), 2.41 (s, 3H)

LR MS (ES+): 456 (M+Na⁺)

LR MS (ES−): 432 (M−H)

Example 285-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid

To a stirred solution of methyl5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

(20 mg, 0.046 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded 3 ml of IM NaOH (3 mmol) solution. The mixture was heated in a 72°C. bath for 3 hours, cooled to room temperature and poured into 50 ml ofwater. 2M HCl was added until pH=4. The resulting precipitates werefiltered, washed with water, and dried in vacuo to give5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid as light gray solid.

Yield: 19 mg, 100%.

LR MS (ES−): 420 (M−H)

Example 29 methyl5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

Similar procedure as Example 33.

¹H NMR (d₆-DMSO): 12.15 (br. s., 1H), 9.74 (s, 1H), 8.43 (d, J=5.6 Hz,1H), 7.81 (d, J=1.8 Hz, 1H), 7.60 (dd, J=6.4, 2.9 Hz, 1H), 7.34-7.50 (m,3H), 7.02-7.18 (m, 2H), 6.75 (dd, J=5.6, 2.3 Hz, 1H), 6.60 (d, J=1.5 Hz,1H), 3.72 (s, 3H), 2.31 (s, 3H)

LR MS (ES+): 458 (M+Na⁺)

LR MS (ES−): 434 (M−H)

Example 30N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 101.

¹H NMR (d₆-DMSO): 11.83 (br. s., 1H), 10.20 (s, 1H), 8.39 (d, J=5.6 Hz,1H), 7.77 (d, J=1.5 Hz, 1H), 7.65-7.72 (m, 2H), 7.37-7.45 (m, 1H), 7.32(d, J=2.1 Hz, 1H), 7.27 (dd, J=2.9, 1.5 Hz, 1H), 6.96-6.99 (m, 1H),6.87-6.92 (m, 1H), 6.71 (dd, J=5.6, 2.3 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H),3.35 (s, 6H), 2.30 (s, 3H)

LR MS (ES+): 501 (M+Na⁺)

LR MS (ES−): 477 (M−H)

Example 31N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide

A mixture of5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid (60 mg, 0.15 mmol), HATU (68 mg, 0.18 mmol) andN,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (10 ml)was stirred at room temperature for 10 minutes, followed by addition of(S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred foranother 10 minutes and poured into 100 ml of water. 2M HCl was addeddropwise until pH=4˜5. The precipitates were filtered, washed with waterand dried in vacuo to giveN-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamideas white solid. Yield: 40 mg, 56%.

¹H NMR (d₆-DMSO): 11.95 (br. s., 1H), 10.21 (s, 1H), 8.41 (d, J=5.6 Hz,1H), 7.77 (d, J=1.8 Hz, 1H), 7.64-7.74 (m, 2H), 7.35-7.51 (m, 2H), 7.29(br. s., 1H), 7.12 (br. s., 1H), 6.90 (dd, J=8.1, 1.3 Hz, 1H), 6.73 (dd,J=5.7, 2.2 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 4.20-4.36 (m, 1H), 3.66-3.88(m, 2H), 3.42-3.60 (m, 3H), 2.30 (s, 3H), 1.66-2.03 (m, 2H)

LR MS (ES+): 495 (M+Na⁺)

LR MS (ES−): 471 (M−H)

Example 325-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid

To a stirred solution of methyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate(1.30 g, 3.12 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) wasadded 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a68° C. bath for 8 hours, cooled to room temperature and poured into 200ml of water. 2M HCl was added until pH=3. The resulting precipitateswere filtered, washed with water, and dried in vacuo to give5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid as white solid.

Yield: 1.20 g, 95%.

¹H NMR (d₆-DMSO): 11.98 (br. s., 1H), 10.22 (s, 1H), 8.42 (d, J=5.6 Hz,1H), 7.79 (d, J=1.2 Hz, 1H), 7.61-7.76 (m, 2H), 7.27-7.51 (m, 3H), 7.04(br. s., 1H), 6.85-6.98 (m, 1H), 6.73 (dd, J=5.7, 2.2 Hz, 1H), 6.59 (d,J=1.5 Hz, 1H), 2.32 (s, 3H)

LR MS (ES−): 402 (M−H)

Example 33 methyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

A mixture of 3-methyl-2-furoic acid (490 mg, 3.88 mmol), HATU (1.71 g,4.5 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol) in anhydrousDMF (10 ml) was stirred at room temperature for 10 minutes, followed byaddition of methyl5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0 g, 3.24mmol). The mixture was stirred at 50° C. for 2 hours and poured into 100ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitateswere filtered, washed with water and dried in vacuo to give methyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylateas white solid. Yield: 1.30 g, 96%.

¹H NMR (d₆-DMSO): 12.15 (br. s., 1H), 10.22 (s, 1H), 8.43 (d, J=5.9 Hz,1H), 7.79 (d, J=1.5 Hz, 1H), 7.68-7.74 (m, 2H), 7.38-7.47 (m, 3H),7.09-7.14 (m, 1H), 6.88-6.94 (m, 1H), 6.75 (dd, J=5.6, 2.3 Hz, 1H), 6.59(d, J=1.5 Hz, 1H), 3.72 (s, 3H), 2.32 (s, 3H)

LR MS (ES+): 440 (M+Na⁺)

LR MS (ES−): 416 (M−H)

Example 343-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide

A mixture of 3-methyl-2-furoic acid (60 mg, 0.48 mmol), HBTU (198 mg,0.52 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in anhydrousDMF (10 ml) was stirred at room temperature for 10 minutes, followed byaddition of 3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}aniline (100 mg, 0.40mmol). The mixture was stirred at 70° C. for 3 hours and poured into 100ml of water. The precipitates were filtered, washed with water and driedin vacuo to give the crude, which was purified by silica gelchromatography eluting with 3-5% MeOH/CHCl₃ to give3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide aswhite solid. Yield: 52 mg, 36%.

¹H NMR (d₆-DMSO): 11.46 (br. s., 1H), 10.19 (s, 1H), 8.36 (d, J=6.2 Hz,1H), 7.77 (d, J=1.8 Hz, 1H), 7.64-7.72 (m, 2H), 7.35-7.44 (m, 1H), 7.28(d, J=2.1 Hz, 1H), 6.86-6.91 (m, 1H), 6.81-6.86 (m, 1H), 6.68-6.74 (m,1H), 6.65 (dd, J=5.7, 2.5 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 6.06-6.13 (m,1H), 2.30 (s, 3H)

LR MS (ES+): 360 (M+H)

LR MS (ES−): 358 (M−H)

Example 35 methyl4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate

Similar procedure as Example 33.

¹H NMR (d₆-DMSO): 12.18 (br. s., 1H), 10.19 (s, 1H), 8.37 (d, J=5.6 Hz,1H), 7.77 (d, J=1.8 Hz, 1H), 7.59-7.72 (m, 3H), 7.33-7.44 (m, 2H),7.25-7.32 (m, 1H), 6.83-6.93 (m, 1H), 6.66 (dd, J=5.6, 2.3 Hz, 1H), 6.57(d, J=1.2 Hz, 1H), 3.76 (s, 3H), 2.30 (s, 3H)

LR MS (ES+): 440 (M+Na⁺)

LR MS (ES−): 416 (M−H)

Example 362-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide

Similar procedure as Example 37.

¹H NMR (d₆-DMSO): 11.44 (br. s., 1H), 10.47 (s, 1H), 8.33 (d, J=5.6 Hz,1H), 7.76-7.86 (m, 2H), 7.46 (dd, J=6.4, 2.1 Hz, 1H), 7.36 (ddd, J=7.9,5.3, 2.1 Hz, 1H), 7.13-7.27 (m, 4H), 6.80-6.87 (m, 1H), 6.66-6.73 (m,1H), 6.60 (dd, J=5.6, 2.3 Hz, 1H), 6.06-6.15 (m, 1H), 2.34 (s, 3H)

LR MS (ES+): 388 (M+H)

LR MS (ES−): 386 (M−H)

Example 373-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide

A mixture of 3-methyl-2-furoic acid (70 mg, 0.55 mmol), HATU (243 mg,0.64 mmol),) tert-butyl2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate (160 mg,0.46 mmol) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) inanhydrous DMF (10 ml) was stirred at 45° C. for 2 hours. The mixture waspoured into 100 ml of water. The precipitates were filtered, washed withwater and dried in vacuo to give the crude, which was dissolved in 5 mlof methylene chloride, followed by addition of trifluoroacetic acid (3ml). The mixture was stirred at room temperature for 16 hours. Thesolvents were evaporated under reduced pressure. The residue waspurified by reversed-phase chromatography with a gradient of 10-50%acetonitrile/water to give3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide aswhite solid.

Yield: 56 mg, 34%.

LR MS (ES+): 360 (M+H)

LR MS (ES−): 358 (M−H)

Preparation of 4-((2-chloropyridin-4-yl)oxy)aniline

A stirred solution of 4-aminophenol (740 mg, 6.8 mmol) in anhydrous DMSO(8 ml) was flushed with nitrogen and treated with IM KOBu^(t)/THFsolution (10 ml, 10 mmol). The mixture was stirred at room temperatureunder nitrogen for 10 minutes. 2,4-dichloropyridine (1.0 g, 6.8 mmol)was added and the mixture was heated at 60° C. for 30 minutes, cooled toroom temperature and poured into 100 ml of water. The resultingprecipitates were filtered, washed with water and dried to give4-((2-chloropyridin-4-yl)oxy)aniline as light brown solid. The materialwas used for the following reactions without further purification.Yield: 1.15 g, 77%.

¹H NMR (d₆-DMSO): 8.21 (d, 1H), 6.77-6.91 (m, 4H), 6.54-6.68 (m, 2H),5.16 (s, 2H)

Preparation of methyl5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of 4-((2-chloropyridin-4-yl)oxy)aniline (2.6 g, 11.78 mmol),methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(6.0 g, 23.90 mmol) and Pd(PPh3)₄ (2.72 g, 2.35 mmol) was added to athick walled reaction vessel and purged with N₂. A solution of 2M K₂CO₃(17.68 mL) was added, followed by DME (90 mL). The reaction vessel wassealed and the mixture stirred at 92° C. for 18 h. The reaction vesselwas cooled to room temperature and the mixture was filtered over celite,washing with EtOAc. The filtrate was concentrated to afford a dark oil,which was purified via column chromatography eluting with 40-80%EtOAc/hexanes to afford methyl5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (2.4 g, 65%yield).

Example 385-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

LR MS (ES+): 573 (MH)

Example 395-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.82 (br. s., 1H), 10.55 (br. s., 1H), 9.05 (d,J=1.8 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.64 (br. s., 1H), 8.37 (d, J=5.6Hz, 1H), 8.23 (t, J=9.2 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.31 (br.s., 1H), 7.26 (dd, J=11.7, 2.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.09(dd, J=11.3, 8.4 Hz, 1H), 6.98-7.05 (m, 2H), 6.76-6.83 (m, 1H), 6.73(dd, J=5.7, 2.5 Hz, 1H), 2.25 (s, 3H)

LR MS (ES−): 478 (M−H)

Example 40{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetateacid

To a stirred solution of methyl{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate(60 mg, 0.1 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded 1 ml of IM NaOH (1.0 mmol) solution. The mixture was stirred atroom temperature for 1 hour and poured into 100 ml of water. 2M HCl wasadded until pH=3. The resulting precipitates were filtered, washed withwater, and dried in vacuo to give{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}aceticacid as white solid. Yield: 50 mg, 86%.

¹H NMR (DMSO-d₆) δ: 12.61 (br s, 1H), 9.15 (s, 1H), 8.98 (t, J=5.9 Hz,1H), 8.43-8.48 (m, 2H), 8.40 (d, J=1.5 Hz, 1H), 8.36 (d, J=1.2 Hz, 1H),7.95 (dd, J=7.6, 1.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.40 (d, J=2.3 Hz, 1H),7.12-7.19 (m, 2H), 7.08 (dd, J=11.3, 8.4 Hz, 1H), 6.73-6.81 (m, 2H),3.88 (d, J=5.9 Hz, 2H), 2.25 (s, 3H)

LR MS (ES−): 519 (M−H)

Example 41 methyl{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate

A mixture of4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylicacid (100 mg, 0.22 mmol), HATU (100 mg, 0.26 mmol) andN,N-diisopropylethylamine (85 mg, 0.66 mmol) in anhydrous DMF (10 ml)was stirred at room temperature for 10 minutes, followed by addition ofglycine methyl ester hydrochloride (41 mg, 0.33 mmol). The mixture wasstirred for another 10 minutes and poured into 100 ml of water. 2M HClwas added dropwise until pH=4˜5. The precipitates were filtered, washedwith water and dried in vacuo to give methyl{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetateas white solid. Yield: 90 mg, 78%.

¹H NMR (DMSO-d₆) δ: 9.17 (s, 1H), 9.10 (t, J=5.9 Hz, 1H), 8.44-8.49 (m,2H), 8.37-8.42 (m, 2H), 7.92-7.98 (m, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.43(d, J=2.1 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.08 (dd, J=11.3, 8.4 Hz,1H), 6.75-6.84 (m, 2H), 3.98 (d, J=5.9 Hz, 2H), 3.63 (s, 3H), 2.25 (s,3H)

LR MS (ES+): 557 (M+Na⁺)

LR MS (ES−): 533 (M−H)

Preparation of methyl4-(4-(4-aminophenoxy)pyridine-2-yl)thiophene-2-carboxylate

A mixture of 4-(4-aminophenoxy)-2-chloropyridine (5.0 g, 22.66 mmol),methyl-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate(9.73 g, 36.25 mmol) and Pd(PPh₃)₄ (5.24 g, 4.53 mmol) was added to athick walled reaction vessel and purged with N2. A solution of 2M K₂CO₃(17.0 mL) was added, followed by dioxane (120 mL). The reaction vesselwas sealed and the mixture stirred at 92° C. for 18 h. The reactionvessel was cooled to room temperature and the mixture was filtered overcelite, washing with EtOAc. The filtrate was concentrated and theresultant dark oil was purified via column chromatography, eluting with40-60% EtOAc/hexanes to afford methyl4-(4-(4-aminophenoxy)pyridine-2-yl)thiophene-2-carboxylate (6.1 g, 82%yield).

Example 42 methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate

To a stirred solution of methyl4-[4-(4-aminophenoxy)pyridin-2-yl]thiophene-2-carboxylate (500 mg, 1.53mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (255 mg, 1.68 mmol). The mixture wasstirred at room temperature for one hour and poured into 200 ml ofwater. The resulting precipitates were filtered, washed with water anddried in vacuo to give the crude, which was purified by silica gelchromatography eluting with 3-5% MeOH/CHCl₃ to give methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylateas off-white solid. Yield: 560 mg, 76%.

¹H NMR (DMSO-d₆) δ: 9.14 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.41-8.47 (m,2H), 8.33 (d, J=1.8 Hz, 1H), 7.96 (d, J=6.2 Hz, 1H), 7.48-7.57 (m, 3H),7.13 (d, J=9.1 Hz, 2H), 7.08 (dd, J=11.4, 8.5 Hz, 1H), 6.76-6.81 (m,1H), 6.74 (dd, J=5.6, 2.3 Hz, 1H), 3.83 (s, 3H), 2.25 (s, 3H)

LR MS (ES+): 500 (M+Na⁺)

LR MS (ES−): 476 (M−H)

Example 43(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoicacid

To a stirred solution oftert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate(30 mg, 0.046 mmol) in 5 ml of methylene chloride was added 2 ml of TFA.The mixture was stirred at room temperature for 1 hour, and evaporatedto dryness. The residue was dissolved in MeOH (3 ml), which was addeddropwise into 100 ml of water with vigorous stirring. The precipitateswere filtered, washed with water and dried to give(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoicacid as white solid. Yield: 20 mg, 74%.

¹H NMR (DMSO-d₆) δ: 12.04 (br. s., 1H), 11.86 (br. s., 1H), 8.97 (s,1H), 8.57 (d, J=2.1 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 8.20 (t, J=9.1 Hz,1H), 7.82 (t, J=5.6 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.46 (br. s., 1H),7.12-7.29 (m, 5H), 6.99-7.04 (m, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.74 (d,J=4.7 Hz, 1H), 4.31 (td, J=8.6, 5.4 Hz, 1H), 2.97-3.11 (m, 2H), 2.26 (s,3H), 2.17-2.25 (m, 2H), 1.87-1.98 (m, 1H), 1.74-1.84 (m, 1H), 0.97 (t,J=7.2 Hz, 3H)

LR MS (ES−): 601 (M−H)

Example 44tert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate

A mixture of(2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoicacid (80 mg, 0.13 mmol), HATU (57 mg, 0.15 mmol) andN,N-diisopropylethylamine (49 mg, 0.38 mmol) in anhydrous DMF (8 ml) wasstirred at room temperature for 10 minutes, followed by addition of 2Methylamine in THF solution (0.1 ml, 0.2 mmol). The mixture was stirredfor another 10 minutes and poured into 100 ml of water. 2M HCl was addeddropwise until pH=5. The precipitates were filtered, washed with waterand dried in vacuo to give the crude, which was purified by silica gelchromatography eluting with 4˜5% MeOH/CHCl₃ to givetert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoateas white solid. Yield: 40 mg, 48%.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 8.95 (s, 1H), 8.56 (br. s., 1H),8.38 (d, J=5.6 Hz, 1H), 8.20 (t, J=9.1 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H),7.77 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.23-7.30 (m, 2H),7.18-7.23 (m, 2H), 7.12-7.18 (m, 2H), 6.98-7.04 (m, 1H), 6.79 (d, J=7.6Hz, 1H), 6.73 (dd, J=5.6, 2.3 Hz, 1H), 4.27-4.35 (m, 1H), 3.01-3.08 (m,2H), 2.26 (s, 3H), 2.17-2.23 (m, 2H), 1.87-1.95 (m, 1H), 1.78 (m, 1H),1.34 (s, 9H), 0.97 (t, J=7.2 Hz, 3H)

LR MS (ES+): 681 (M+Na⁺)

LR MS (ES−): 657 (M−H)

Example 45 (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoicacid

To a stirred solution of (S)-5-tert-butyl 1-methyl2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate(120 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded 1 ml of IM NaOH (1 mmol) solution. The mixture was stirred at roomtemperature for 30 minutes, and poured into 100 ml of water. 2M HCl wasadded dropwise until pH=4. The resulting precipitates were filtered,washed with water, and dried in vacuo to give(2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoicacid as white solid. Yield: 100 mg, 85%.

¹H NMR (DMSO-d₆) δ: 12.49 (br. s., 1H), 11.84 (br. s., 1H), 8.98 (s,1H), 8.58 (d, J=2.3 Hz, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.20 (t, J=9.1 Hz,1H), 7.89 (br. s., 1H), 7.42 (br. s., 1H), 7.28 (s, 1H), 7.25 (dd,J=11.7, 2.6 Hz, 1H), 7.20-7.23 (m, 2H), 7.11-7.18 (m, 2H), 7.01 (dd,J=9.0, 1.6 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.73 (dd, J=5.6, 2.3 Hz,1H), 4.23-4.34 (m, 1H), 2.23-2.28 (m, 2H), 2.26 (s, 3H), 1.95-2.03 (m,1H), 1.80-1.88 (m, 1H), 1.35 (s, 9H)

LR MS (ES+): 654 (M+Na⁺)

LR MS (ES−): 630 (M−H)

Example 46 (S)-5-tert-butyl 1-methyl2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

A mixture of5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid (500 mg, 1.1 mmol), HATU (500 mg, 1.32 mmol) andN,N-diisopropylethylamine (426 mg, 3.3 mmol) in anhydrous DMF (8 ml) wasstirred at room temperature for 10 minutes, followed by addition ofL-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (334 mg, 1.32mmol). The mixture was stirred for another 10 minutes and poured into200 ml of water. 2M HCl was added dropwise until pH=5. The precipitateswere filtered, washed with water and dried in vacuo to give the crude,which was purified by silica gel chromatography eluting with 3-5%MeOH/CHCl₃ to give (S)-5-tert-butyl 1-methyl2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioateas off-white solid. Yield: 380 mg, 52%.

¹H NMR (DMSO-d₆) δ: 11.87 (br. s., 1H), 8.96 (s, 1H), 8.56 (br. s., 1H),8.38 (d, J=5.6 Hz, 1H), 8.20 (t, J=8.9 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H),7.44 (br. s., 1H), 7.23-7.29 (m, 2H), 7.18-7.23 (m, 2H), 7.11-7.17 (m,2H), 7.01 (d, J=8.8 Hz, 1H), 6.79 (d, J=7.0 Hz, 1H), 6.70-6.76 (m, 1H),4.32-4.41 (m, 1H), 3.60 (s, 3H), 2.23-2.31 (m, 5H), 1.93-2.03 (m, 1H),1.81-1.91 (m, 1H), 1.35 (s, 9H)

LR MS (ES+): 646 (MH), 668 (M+Na⁺)

LR MS (ES−): 644 (M−H)

Example 47 bis(2-hydroxyethyl)2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

LR MS (ES+): 686 (M+Na⁺)

LR MS (ES−): 662 (M−H), 561

Example 483-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.90 (br. s., 1H), 8.99 (s, 1H), 8.59 (br. s., 1H),8.40 (d, J=5.9 Hz, 1H), 8.22 (t, J=9.0 Hz, 1H), 7.90-7.96 (m, 1H), 7.40(br. s., 1H), 7.25-7.30 (m, 2H), 7.21 (d, J=7.0 Hz, 2H), 7.15 (t, J=7.8Hz, 2H), 7.03 (d, J=9.1 Hz, 1H), 6.79 (d, J=7.0 Hz, 2H), 3.32-3.37 (m,2H), 2.43 (t, J=7.0 Hz, 2H), 2.26 (s, 3H)

LR MS (ES−): 516 (M−H)

Example 492-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioicacid

¹H NMR (DMSO-d₆) δ: 12.43 (br. s., 2H), 11.89 (br. s., 1H), 8.97 (br.s., 1H), 8.57 (br. s., 1H), 8.39 (d, J=5.3 Hz, 1H), 8.20 (t, J=8.8 Hz,1H), 7.97 (d, J=7.6 Hz, 1H), 7.46 (br. s., 1H), 7.11-7.31 (m, 4H), 7.02(d, J=9.1 Hz, 1H), 6.79 (d, J=7.0 Hz, 1H), 6.75 (br. s., 1H), 4.32 (br.s., 1H), 2.30 (t, J=7.2 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.86 (m,2H)

LR MS (ES−): 574 (M−H)

Example 50 methyl1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate

Similar procedure as Example 132.

LR MS (ES+): 615 (MH), 637 (M+Na⁺)

LR MS (ES−): 613 (M−H)

Example 515-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

LR MS (ES+): 573 (MH), 595 (M+Na⁺)

LR MS (ES−): 571 (M−H)

Example 52N-{4-[(2,3-dihydroxypropyl)(methyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

¹H NMR (DMSO-d₆) δ: 11.70-11.82 (m, 1H), 9.24 (s, 1H), 8.50 (d, J=2.1Hz, 1H), 8.35 (d, J=5.9 Hz, 1H), 7.93-7.98 (m, 1H), 7.85 (dt, J=14.5,5.5 Hz, 1H), 7.54 (d, J=9.1 Hz, 2H), 7.34 (br. s., 1H), 7.10-7.15 (m,3H), 7.08 (dd, J=11.2, 8.5 Hz, 1H), 7.01-7.05 (m, 1H), 6.73-6.82 (m,1H), 6.67 (dd, J=5.6, 2.3 Hz, 1H), 4.87 (d, J=5.3 Hz, 1H), 4.60-4.69 (m,1H), 4.46 (t, J=5.9 Hz, 1H), 3.55-3.65 (m, 2H), 3.20-3.27 (m, 2H),3.10-3.19 (m, 2H), 2.96 (s, 1H), 2.79 (s, 2H), 2.27-2.35 (m, 1H), 2.24(s, 3H), 1.62-1.72 (m, 2H)

LR MS (ES+): 619 (MH), 641 (M+Na⁺)

LR MS (ES−): 617 (M−H)

Example 535-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypiperidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

LR MS (ES+): 637 (M+Na⁺)

LR MS (ES−): 613 (M−H)

Example 54N-{4-[(2,3-dihydroxypropyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

¹H NMR (DMSO-d₆) δ: 11.77 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J=2.3 Hz,1H), 8.35 (d, J=5.9 Hz, 1H), 7.96 (dd, J=7.9, 2.1 Hz, 1H), 7.84 (t,J=5.6 Hz, 1H), 7.77 (t, J=5.9 Hz, 1H), 7.51-7.57 (m, 2H), 7.33 (dd,J=3.1, 1.6 Hz, 1H), 7.11-7.16 (m, 3H), 7.08 (dd, J=11.3, 8.4 Hz, 1H),7.01-7.05 (m, 1H), 6.75-6.82 (m, 1H), 6.68 (dd, J=5.7, 2.5 Hz, 1H), 4.68(d, J=5.0 Hz, 1H), 4.46 (t, J=5.9 Hz, 1H), 3.41-3.47 (m, 1H), 3.20-3.26(m, 2H), 3.09-3.19 (m, 3H), 2.90-2.97 (m, 1H), 2.25 (s, 3H), 2.10 (t,J=7.6 Hz, 2H), 1.66 (quin, J=7.3 Hz, 2H)

LR MS (ES+): 605 (MH), 627 (M+Na⁺)

LR MS (ES−): 603 (M−H)

Example 55N-(4-amino-4-oxobutyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

¹H NMR (DMSO-d₆) δ: 11.92 (br. s., 1H), 9.20 (br. s., 1H), 8.48 (d,J=1.8 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H),7.89 (br. s., 1H), 7.56 (d, J=8.8 Hz, 2H), 7.42 (br. s., 1H), 7.18-7.28(m, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.08 (dd, J=11.4, 8.5 Hz, 1H), 6.78(ddd, J=7.5, 5.0, 2.2 Hz, 2H), 6.68 (br. s., 1H), 3.14 (q, J=6.7 Hz,2H), 2.25 (s, 3H), 2.05 (t, J=7.5 Hz, 2H), 1.66 (quin, J=7.3 Hz, 2H)

LR MS (ES+): 553 (M+Na⁺)

LR MS (ES−): 529 (M−H)

Example 56N-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 9.15 (s, 1H), 8.46 (br. s., 1H),8.36 (d, J=5.9 Hz, 1H), 8.14 (t, J=6.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H),7.67 (t, J=5.6 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.38 (br. s., 1H), 7.13(d, J=8.8 Hz, 3H), 7.03-7.11 (m, 2H), 6.75-6.82 (m, 1H), 6.69 (dd,J=5.6, 2.3 Hz, 1H), 4.70 (d, J=5.0 Hz, 1H), 4.47 (t, J=5.7 Hz, 1H), 3.76(d, J=5.6 Hz, 2H), 3.45 (dq, J=11.2, 5.5 Hz, 1H), 3.16-3.27 (m, 3H),2.93-3.00 (m, 1H), 2.25 (s, 3H)

LR MS (ES+): 577 (MH), 599 (M+Na⁺)

LR MS (ES−): 575 (M−H)

Example 57 5-(2,3-dihydroxypropyl) 1-methyl2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

Similar procedure as Example 58.

¹H NMR (DMSO-d₆) δ: 11.86 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J=2.3 Hz,1H), 8.36 (d, J=5.6 Hz, 1H), 8.08-8.17 (m, 1H), 7.96 (dd, J=7.9, 1.8 Hz,1H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (br. s., 1H), 7.04-7.21 (m, 4H), 6.78(dt, J=5.7, 2.7 Hz, 1H), 6.68 (dd, J=5.6, 2.3 Hz, 1H), 4.83 (d, J=5.3Hz, 1H), 4.58 (t, J=5.7 Hz, 1H), 4.36-4.45 (m, 1H), 3.95-4.06 (m, 2H),3.88 (dd, J=11.0, 6.6 Hz, 1H), 3.60 (s, 3H), 3.28-3.35 (m, 2H), 2.40 (t,J=7.6 Hz, 2H), 2.25 (s, 3H), 1.99-2.10 (m, 1H), 1.88-1.95 (m, 1H), 1.15(t, J=7.0 Hz, 1H)

LR MS (ES+): 664 (MH), 686 (M+Na⁺)

Example 58 bis(2,3-dihydroxypropyl)2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

A mixture of2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioicacid (60 mg, 0.10 mmol), glycerol (0.5 ml),1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl,37 mg, 0.19 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) inanhydrous THF (10 ml) was stirred at 60° C. for 3 hours. The mixture wascooled to room temperature, concentrated and purified by silica gelchromatography eluting with a gradient of 10-15% MeOH/CHCl₃ to givebis(2,3-dihydroxypropyl)2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioateas colorless oil. Yield: 40 mg, 53%.

LR MS (ES+): 746 (M+Na⁺)

LR MS (ES−): 722 (M−H)

Example 594-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-methoxy-5-oxopentanoicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.98 (br. s., 1H), 9.19 (s, 1H), 8.48 (d, J=2.6 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.95 (dd, J=7.8,1.9 Hz, 1H), 7.53-7.57 (m, 2H), 7.47-7.52 (m, 1H), 7.24 (br. s., 1H),7.19 (br. s., 1H), 7.15 (d, J=8.8 Hz, 2H), 7.08 (dd, J=11.3, 8.4 Hz,1H), 6.72-6.81 (m, 2H), 4.38 (ddd, J=9.5, 7.5, 5.3 Hz, 1H), 3.60 (s,3H), 2.31 (t, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.95-2.05 (m, 1H), 1.82-1.93(m, J=14.0, 9.6, 7.0, 7.0 Hz, 1H)

LR MS (ES−): 588 (M−H)

Example 60N-[4-(ethylamino)-4-oxobutyl]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

¹H NMR (DMSO-d₆) δ: 11.96 (br. s., 1H), 9.20 (s, 1H), 8.48 (d, J=2.6 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.89 (br. s.,1H), 7.76 (t, J=5.3 Hz, 1H), 7.53-7.58 (m, 2H), 7.44 (br. s., 1H), 7.23(br. s., 1H), 7.13-7.19 (m, 3H), 7.08 (dd, J=11.3, 8.4 Hz, 1H),6.75-6.84 (m, 2H), 3.11-3.17 (m, 2H), 3.01 (qd, J=7.2, 5.6 Hz, 2H), 2.25(s, 3H), 2.05 (t, J=7.5 Hz, 2H), 1.66 (quin, J=7.3 Hz, 2H), 0.96 (t,J=7.2 Hz, 3H)

LR MS (ES+): 559 (MH), 581 (M+Na⁺)

LR MS (ES−): 557 (M−H)

Example 615-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide

A mixture of4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoicacid (60 mg, 0.1 mmol), HATU (50 mg, 0.13 mmol) andN,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (8 ml) wasstirred at room temperature for 10 minutes, followed by addition of(R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred foranother 10 minutes and poured into 100 ml of water. 2M HCl was addeddropwise until pH=4˜5. The precipitates were filtered, washed with waterand dried in vacuo to give5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamideas white solid. Yield: 40 mg, 59%.

¹H NMR (DMSO-d₆) δ: 11.97 (br. s., 1H), 9.31 (s, 1H), 8.53 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.91 (d,J=4.4 Hz, 1H), 7.54-7.59 (m, 2H), 7.42-7.48 (m, 1H), 7.24 (br. s., 1H),7.16 (d, J=8.8 Hz, 2H), 7.05-7.10 (m, 1H), 6.78 (ddd, J=7.5, 5.0, 2.2Hz, 2H), 4.24-4.28 (m, OH), 4.16-4.21 (m, 1H), 3.40-3.48 (m, 2H), 3.35(ddd, J=11.6, 8.4, 3.5 Hz, 1H), 3.25-3.30 (m, 1H), 3.14-3.25 (m, 4H),2.25 (s, 3H), 2.23-2.27 (m, 1H), 2.20 (t, J=7.9 Hz, 1H), 1.84-1.92 (m,1H), 1.75-1.82 (m, 1H), 1.65-1.73 (m, 2H)

LR MS (ES+): 601 (MH), 623 (M+Na⁺)

LR MS (ES−): 599 (M−H)

Example 625-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(hydroxyamino)-4-oxobutyl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

¹H NMR (DMSO-d₆) δ: 11.92 (br. s., 1H), 10.33 (s, 1H), 9.18 (s, 1H),8.47 (d, J=2.6 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 7.95 (dd, J=7.9, 1.8 Hz,1H), 7.87-7.92 (m, 1H), 7.51-7.58 (m, 2H), 7.38-7.46 (m, 1H), 7.21 (br.s., 1H), 7.11-7.18 (m, 3H), 7.05-7.11 (m, 1H), 6.72-6.82 (m, 2H), 3.14(q, J=6.7 Hz, 2H), 2.25 (s, 3H), 1.96 (t, J=7.6 Hz, 2H), 1.66 (quin,J=7.3 Hz, 2H)

LR MS (ES+): 547 (MH), 569 (M+Na⁺)

LR MS (ES−): 545 (M−H)

Example 632-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.42 (br. s., 1H), 12.12 (br. s., 1H), 11.86 (br.s., 1H), 9.15 (s, 1H), 8.46 (d, J=2.6 Hz, 1H), 8.37 (d, J=5.6 Hz, 1H),7.93-8.01 (m, 2H), 7.51-7.58 (m, 2H), 7.44 (br. s., 1H), 7.18 (s, 1H),7.11-7.16 (m, 3H), 7.08 (dd, J=11.3, 8.4 Hz, 1H), 6.75-6.82 (m, 1H),6.69 (d, J=3.8 Hz, 1H), 4.32 (ddd, J=9.7, 7.9, 5.0 Hz, 1H), 2.30 (t,J=7.6 Hz, 2H), 2.25 (s, 3H), 1.96-2.05 (m, 1H), 1.80-1.91 (m, J=14.0,9.8, 7.2, 7.2 Hz, 1H)

LR MS (ES−): 574 (M−H)

Example 64 dimethyl2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.27 (br. s., 1H), 9.33 (br. s., 1H), 8.50-8.57 (m,1H), 8.44 (d, J=6.2 Hz, 1H), 8.23 (d, J=6.7 Hz, 1H), 7.95 (d, J=6.5 Hz,1H), 7.64 (br. s., 1H), 7.58 (d, J=8.8 Hz, 2H), 7.39 (br. s., 2H), 7.19(d, J=8.8 Hz, 2H), 7.08 (dd, J=11.2, 8.2 Hz, 1H), 6.92 (br. s., 1H),6.79 (d, J=5.6 Hz, 1H), 4.35-4.43 (m, 1H), 3.60 (s, 3H), 3.55 (s, 3H),2.40 (t, J=7.5 Hz, 2H), 2.22-2.28 (m, 3H), 2.00-2.10 (m, 1H), 1.88-1.97(m, 1H)

LR MS (ES+): 626 (M+Na⁺)

LR MS (ES−): 602 (M−H)

Example 651-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.47 (br. s., 1H), 11.85-12.01 (m, 1H), 9.05 (d,J=1.8 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 8.22 (t,J=9.1 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.41 (br. s., 1H),7.21-7.32 (m, 2H), 7.06-7.14 (m, 2H), 7.01 (dd, J=9.0, 1.6 Hz, 1H), 6.79(ddd, J=7.6, 5.1, 1.9 Hz, 1H), 6.65-6.76 (m, 1H), 2.97-3.93 (m, 5H),2.25 (s, 3H), 1.93-2.19 (m, 2H)

LR MS (ES+): 562 (MH), 584 (M+Na⁺)

LR MS (ES−): 560 (M−H)

Example 664-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoicacid

To a stirred solution of ethyl4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate(45 mg, 0.078 mmol) in 10 ml of THF was added 3 ml of IM NaOH (3.0mmol). The mixture was heated at 60° C. for 3 hours, cooled to roomtemperature and poured into 100 ml of water. 2M HCl was added untilpH=5. The precipitates were filtered, washed with water, and dried togive4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoicacid as grey solid. Yield: 40 mg, 93%.

¹H NMR (DMSO-d₆) δ: 11.99 (br. s., 1H), 11.82 (br. s., 1H), 9.06 (d,J=2.1 Hz, 1H), 8.94 (d, J=2.6 Hz, 1H), 8.38 (d, J=5.9 Hz, 1H), 8.23 (t,J=9.1 Hz, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.85 (t, J=5.7 Hz, 1H),7.37 (br. s., 1H), 7.27 (dd, J=11.7, 2.6 Hz, 1H), 7.19 (s, 1H), 7.09(dd, J=11.3, 8.4 Hz, 2H), 7.02 (dd, J=8.9, 1.6 Hz, 1H), 6.77-6.82 (m,1H), 6.73-6.77 (m, 1H), 3.16 (q, J=6.7 Hz, 2H), 2.25 (s, 3H), 2.22 (t,J=7.3 Hz, 2H), 1.67 (quin, J=7.2 Hz, 2H)

LR MS (ES−): 548 (M−H)

Example 67 ethyl4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.99 (br. s., 1H), 9.09 (d, J=1.5 Hz, 1H), 8.96 (d,J=2.3 Hz, 1H), 8.42 (d, J=6.2 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (dd,J=7.8, 2.2 Hz, 1H), 7.86-7.94 (m, 1H), 7.46 (br. s., 1H), 7.25-7.34 (m,2H), 7.22 (br. s., 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 7.02-7.07 (m,1H), 6.87 (br. s., 1H), 6.76-6.82 (m, 1H), 4.01 (q, J=7.1 Hz, 2H),3.13-3.21 (m, 2H), 2.30 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 1.70 (quin,J=7.2 Hz, 2H), 1.14 (t, J=7.04 Hz, 3H)

LR MS (ES+): 578 (MH), 600 (M+Na⁺)

LR MS (ES−): 576 (M−H)

Example 684-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoicacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ:12.00 (br. s., 1H), 11.82 (br. s., 1H), 8.97 (s, 1H),8.57 (d, J=2.3 Hz, 1H), 8.38 (d, J=5.9 Hz, 1H), 8.21 (t, J=9.1 Hz, 1H),7.85 (t, J=5.7 Hz, 1H), 7.37 (br. s., 1H), 7.24-7.29 (m, 2H), 7.17-7.23(m, 2H), 7.13-7.17 (m, 1H), 7.10 (br. s., 1H), 7.02 (dd, J=8.8, 1.8 Hz,1H), 6.79 (d, J=7.3 Hz, 1H), 6.75 (br. s., 1H), 3.16 (q, J=6.7 Hz, 2H),2.26 (s, 3H), 2.22 (t, J=7.3 Hz, 2H), 1.67 (quin, J=7.2 Hz, 2H)

LR MS (ES+): 532 (MH), 554 (M+Na⁺)

LR MS (ES−): 530 (M−H)

Example 693-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoicacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ: 11.93 (br. s., 2H), 9.08 (br. s., 1H), 8.96 (d,J=1.8 Hz, 1H), 8.41 (d, J=5.9 Hz, 1H), 8.25 (t, J=8.9 Hz, 1H), 7.98 (d,J=7.9 Hz, 1H), 7.94 (br. s., 1H), 7.43 (d, J=2.1 Hz, 1H), 7.29 (d,J=10.3 Hz, 1H), 7.24 (br. s., 1H), 7.17 (br. s., 1H), 7.09 (dd, J=11.3,8.4 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.83 (br. s., 1H), 6.76-6.81 (m,1H), 3.33-3.38 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 2.25 (s, 3H)

LR MS (ES−): 534 (M−H)

Example 70N-ethyl-5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.98 (br. s., 1H), 9.11 (s, 1H), 8.67 (br. s., 1H),8.41 (d, J=5.9 Hz, 1H), 8.23 (t, J=9.1 Hz, 1H), 7.87 (t, J=5.0 Hz, 1H),7.44 (br. s., 1H), 7.25-7.32 (m, 3H), 7.18-7.25 (m, 2H), 7.12-7.17 (m,1H), 7.04 (dd, J=9.0, 1.6 Hz, 1H), 6.85 (br. s., 1H), 6.79 (d, J=7.3 Hz,1H), 3.15-3.22 (m, 2H), 2.26 (s, 3H), 1.05 (t, J=7.2 Hz, 3H)

LR MS (ES+): 474 (MH), 496 (M+Na⁺)

LR MS (ES−): 472 (M−H)

Example 71{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}aceticacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ:11.84 (br. s., 1H), 9.23 (s, 1H), 8.73 (d, J=1.5 Hz,1H), 8.38 (d, J=5.6 Hz, 1H), 8.18 (t, J=9.1 Hz, 1H), 8.12 (t, J=5.4 Hz,1H), 7.38 (dd, J=2.9, 1.8 Hz, 1H), 7.28 (s, 1H), 7.21-7.26 (m, 2H), 7.19(d, J=2.3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.08-7.11 (m, 1H), 7.01 (dd,J=9.0, 2.5 Hz, 1H), 6.78 (d, J=7.3 Hz, 1H), 6.73 (dd, J=5.9, 2.3 Hz,1H), 3.78 (d, J=5.9 Hz, 2H), 2.25 (s, 3H)

LR MS (ES−): 502 (M−H)

Example 72 methyl{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.87 (br. s., 1H), 8.96 (s, 1H), 8.56 (d, J=2.3 Hz,1H), 8.38 (d, J=5.9 Hz, 1H), 8.31 (t, J=6.0 Hz, 1H), 8.20 (t, J=9.1 Hz,1H), 7.39 (dd, J=3.2, 1.8 Hz, 1H), 7.24-7.29 (m, 2H), 7.21 (d, J=8.2 Hz,1H), 7.19 (d, J=2.3 Hz, 1H), 7.13-7.17 (m, 1H), 7.08-7.10 (m, 1H), 7.01(dd, J=8.5, 2.1 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.74 (dd, J=5.9, 2.3Hz, 1H), 3.90 (d, J=5.9 Hz, 2H), 3.60 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES−): 516 (M−H)

Example 731-(2-fluoro-4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-(3-methylphenyl)urea

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.87 (br. s., 1H), 8.97 (s, 1H), 8.56 (d, J=2.1 Hz,1H), 8.37 (d, J=5.9 Hz, 1H), 8.18 (t, J=9.1 Hz, 1H), 7.38 (d, J=2.3 Hz,1H), 7.18-7.30 (m, 4H), 7.12-7.17 (m, 1H), 7.08 (d, J=18.8 Hz, 1H), 6.99(dt, J=7.6, 1.5 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.68 (dd, J=5.6, 2.3Hz, 1H), 4.90 (d, J=9.4 Hz, 1H), 4.30 (br. s., 1H), 3.68-3.82 (m, 2H),3.42-3.54 (m, 2H), 2.26 (s, 3H), 1.72-1.97 (m, 2H)

LR MS (ES+): 516 (MH), 538 (M+Na⁺)

LR MS (ES−): 514 (M−H)

Example 741-{2-fluoro-4-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3-(3-methylphenyl)urea

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 8.96 (s, 1H), 8.55 (d, J=2.3 Hz,1H), 8.37 (d, J=5.6 Hz, 1H), 8.19 (t, J=9.1 Hz, 1H), 7.34 (d, J=2.3 Hz,1H), 7.27 (s, 1H), 7.19-7.25 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.12 (br.s., 1H), 6.97-7.01 (m, 1H), 6.90 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.68(dd, J=5.7, 2.2 Hz, 1H), 4.87 (br. s., 1H), 4.04 (br. s., 1H), 3.85 (br.s., 1H), 3.41-3.52 (m, 1H), 3.07 (t, J=10.1 Hz, 1H), 2.26 (s, 3H),1.78-1.90 (m, 1H), 1.67 (td, J=8.8, 4.7 Hz, 1H), 1.30-1.43 (m, 2H)

LR MS (ES+): 530 (MH), 552 (M+Na⁺)

LR MS (ES−): 528 (M−H)

Example 755-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 134.

¹H NMR (DMSO-d₆) δ: 12.04 (br. s., 1H), 11.87 (br. s., 1H), 8.97 (br.s., 1H), 8.56 (br. s., 1H), 8.39 (d, J=5.9 Hz, 1H), 8.20 (t, J=9.1 Hz,1H), 7.36 (br. s., 2H), 7.19-7.30 (m, 3H), 7.12-7.17 (m, 1H), 7.08 (br.s., 1H), 7.00 (d, J=8.8 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.73 (br. s.,1H), 2.26 (s, 3H)

LR MS (ES+): 469 (MH)

Example 76 methyl5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

¹H NMR (DMSO-d₆) δ: 12.11 (br. s., 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.38(d, J=5.9 Hz, 1H), 8.19 (t, J=9.1 Hz, 1H), 7.42 (dd, J=3.1, 1.6 Hz, 1H),7.37 (d, J=2.1 Hz, 1H), 7.28 (s, 1H), 7.19-7.26 (m, 2H), 7.12-7.17 (m,1H), 7.09-7.12 (m, 1H), 7.00 (dd, J=9.1, 2.3 Hz, 1H), 6.79 (d, J=7.3 Hz,1H), 6.72 (dd, J=5.6, 2.3 Hz, 1H), 3.69 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 461 (MH), 483 (M+Na⁺)

LR MS (ES−): 459 (M−H)

Example 77

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.92 (br. s., 1H), 9.20 (s, 1H), 8.48 (br. s., 1H),8.38 (d, J=5.6 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.92 (br. s., 1H), 7.55(d, J=8.8 Hz, 2H), 7.43 (br. s., 1H), 7.20 (br. s., 1H), 7.11-7.17 (m,3H), 7.08 (dd, J=11.2, 8.5 Hz, 1H), 6.73-6.81 (m, 2H), 3.41-3.48 (m,12H), 3.34-3.39 (m, 2H), 3.31 (q, J=5.8 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 622 (MH), 644 (M+Na⁺)

LR MS (ES−): 620 (M−H)

Example 784-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoicacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ: 11.83 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.95-8.02 (m, 1H), 7.88 (t, J=5.6 Hz, 1H),7.57 (d, J=9.1 Hz, 2H), 7.38 (br. s., 1H), 7.16 (d, J=9.1 Hz, 2H),7.06-7.17 (m, 3H), 6.77-6.85 (m, 1H), 6.67-6.76 (m, 1H), 3.16-3.22 (m,2H), 2.28 (s, 3H), 2.25 (t, J=7.3 Hz, 2H), 1.70 (quin, J=7.2 Hz, 2H)

LR MS (ES+): 532 (MH)

LR MS (ES−): 530 (M−H)

Example 79 ethyl4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate

Similar procedure as Example 132.

LR MS (ES+): 560 (MH), 582 (M+Na⁺)

LR MS (ES−): 558 (M−H)

Preparation of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine

2,4-Dichloropyrdine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g,60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixturestirred under nitrogen at room temperature for 18 h. Water (300 mL) wasadded and the slurry stirred for 30 min. The resulting solid wasfiltered, washed with water and vacuum dried at room temperature.Recrystallization from ethyl acetate (35 mL), filtered hot, then cooledgave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield).

Preparation of1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea

To a stirred solution of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine(300 mg, 1.27 mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (210 mg, 1.39 mmol). The mixture wasstirred at 60° C. for 5 hours, and poured into 100 ml of water. Theprecipitates were filtered, washed with water (50 ml), and dried to givethe crude, which was purified by silica gel chromatography eluting with2-3% MeOH/CHCl₃ to give1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-ureaas white solid. Yield: 410 mg, 83%.

¹H NMR (DMSO-d₆) δ: 9.37 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.17 (d, J=5.9Hz, 1H), 7.89-8.01 (m, 1H), 7.58-7.70 (m, 2H), 7.47-7.59 (m, 2H), 7.10(dd, J=11.4, 8.2 Hz, 1H), 6.94-7.03 (m, 2H), 6.82 (dd, J=4.8, 2.2 Hz,1H), 2.26 (s, 3H)

Example 805-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid

To a stirred solution of methyl5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate(86 mg, 0.18 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) wasadded 2 ml of 1M NaOH (2 mmol) solution. The mixture was heated in a 66°C. bath for 7 hours, cooled to room temperature and poured into 100 mlof water. 2M HCl was added until pH=3. The resulting precipitates werefiltered, washed with water, and dried in vacuo to give5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid as light brown solid. Yield: 73 mg, 88%.

¹H NMR (DMSO-d₆) δ: 12.01 (br. s., 1H), 9.37 (s, 1H), 8.56 (d, J=1.8 Hz,1H), 8.27 (d, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.44-7.68 (m, 5H), 7.36 (br.s., 1H), 7.10 (dd, J=11.1, 8.5 Hz, 1H), 6.94 (br. s., 1H), 6.81 (br. s.,1H), 6.69 (d, J=5.3 Hz, 1H), 2.26 (s, 3H)

LR MS (ES−): 461 (M−H)

Example 813-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoicacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ: 12.12 (br. s., 1H), 11.81 (br. s., 1H), 9.15 (s,1H), 8.46 (br. s., 1H), 8.36 (d, J=5.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H),7.92 (t, J=5.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.35 (br. s., 1H), 7.13(dd, J=6.6, 2.2 Hz, 3H), 7.08 (dd, J=11.2, 8.5 Hz, 1H), 7.04 (br. s.,1H), 6.75-6.82 (m, 1H), 6.70 (d, J=3.2 Hz, 1H), 3.32-3.41 (m, 2H), 2.43(t, J=7.0 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES−): 516 (M−H)

Example 824-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoicacid

To a stirred solution of methyl4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoate(5 mg, 0.0087 mol) in MeOH (3 ml) was added IM NaOH (0.5 ml, 0.5 mmol).The mixture was stirred at room temperature for 30 minutes, and pouredinto 30 ml of water. 2M HCl was added dropwise until pH=4. Theprecipitates were filtered, washed with water and dried to give4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoicacid as off-white solid. Yield: 5 mg, 100%.

LR MS (ES+): 576 (MH), 598 (M+Na⁺)

LR MS (ES−): 574 (M−H)

Example 831-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.04 (br. s., 1H), 9.16 (s, 1H), 8.46 (d, J=2.3 Hz,1H), 8.39 (d, J=5.6 Hz, 1H), 7.93-7.99 (m, 1H), 7.54 (d, J=9.1 Hz, 2H),7.41 (br. s., 1H), 7.33 (br. s., 1H), 7.14 (d, J=8.8 Hz, 2H), 7.08 (dd,J=11.3, 8.4 Hz, 1H), 6.75-6.82 (m, 1H), 6.72 (br. s., 1H), 2.98-3.93 (m,5H), 2.25 (s, 3H), 1.93-2.19 (m, 2H)

LR MS (ES+): 544 (MH), 566 (M+Na⁺)

LR MS (ES−): 542 (M−H)

Example 84{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}aceticacid

Similar procedure as Example 66.

¹H NMR (DMSO-d₆) δ: 12.42 (br. s., 1H), 11.85 (br. s., 1H), 9.15 (s,1H), 8.47 (d, J=2.1 Hz, 1H), 8.37 (d, J=5.9 Hz, 1H), 8.21 (t, J=6.0 Hz,1H), 7.90-8.03 (m, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.38 (br. s., 1H),7.02-7.21 (m, 5H), 6.74-6.84 (m, 1H), 6.70 (dd, J=5.6, 2.3 Hz, 1H), 3.82(d, J=5.9 Hz, 2H), 2.26 (s, 3H)

LR MS (ES+): 504 (MH), 526 (M+Na⁺)

LR MS (ES−): 502 (M−H)

Example 85 methyl{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.00 (br. s., 1H), 9.18 (s, 1H), 8.48 (d, J=2.1 Hz,1H), 8.29-8.44 (m, 2H), 7.97 (d, J=7.9 Hz, 1H), 7.56 (d, J=9.1 Hz, 2H),7.46 (br. s., 1H), 7.02-7.27 (m, 5H), 6.79 (d, J=2.1 Hz, 2H), 3.91 (d,J=6.2 Hz, 2H), 3.61 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES−): 516 (M−H)

Example 861-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidine-4-sulfonicacid

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.41 (br. s., 1H), 9.24 (s, 1H), 8.46-8.53 (m, 2H),7.91-7.98 (m, 1H), 7.54-7.64 (m, 3H), 7.45 (br. s., 1H), 7.30 (br. s.,1H), 7.22 (d, J=8.8 Hz, 2H), 7.08 (dd, J=11.2, 8.2 Hz, 1H), 7.02 (br.s., 1H), 6.75-6.82 (m, 1H), 4.29 (br. s., 2H), 3.52 (br. s., 2H),2.48-2.56 (m, 1H), 2.25 (s, 3H), 1.93 (d, J=12.6 Hz, 2H), 1.45 (br. s.,2H)

LR MS (ES+): 616 (M+Na⁺)

LR MS (ES−): 592 (M−H)

Example 87 methyl4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoate

Similar procedure as Example 101.

LR MS (ES+): 590 (MH), 612 (M+Na⁺)

Example 88 methyl5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate

A mixture of1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea(410 mg, 1.06 mmol),methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate(532 mg, 2.12 mmol) and PdCl₂(dppf).CH₂Cl₂ (10 mg, 0.012 mmol) was addedto a thick-walled reaction vessel and purged with N₂. A solution of 2MNa₂CO₃ (1.0 mL) was added, followed by DMSO (10 mL). The reaction vesselwas sealed and the mixture stirred at 95° C. for 16 h. The reactionvessel was cooled to room temperature and the mixture was poured into100 ml of water. The precipitates were filtered, washed with water anddried to give the crude, which was purified via silica gelchromatography eluting with 2-5% MeOH/CHCl₃ to afford methyl5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylateas off-white solid. Yield: 100 mg, 20% yield.

LR MS (ES+): 477 (MH), 499 (M+Na⁺)

Example 89N-methyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.88 (br. s., 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.37(d, J=5.9 Hz, 1H), 7.82 (d, J=4.4 Hz, 1H), 7.52-7.58 (m, 2H), 7.37 (br.s., 1H), 7.27 (s, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.18 (br. s., 1H),7.11-7.15 (m, 3H), 7.08 (br. s., 1H), 6.71-6.80 (m, 2H), 2.67 (d, J=4.7Hz, 3H), 2.25 (s, 3H)

LR MS (ES+): 442 (MH), 464 (M+Na⁺)

LR MS (ES−): 440 (M−H)

Example 901-{4-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3-(3-methylphenyl)urea

Similar procedure as Example 132.

LR MS (ES+): 512 (MH), 534 (M+Na⁺)

LR MS (ES−): 510 (M−H)

Example 911-{4-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3-(3-methylphenyl)urea

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.88 (br. s., 1H), 8.74 (s, 1H), 8.58 (s, 1H), 8.36(d, J=5.6 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 6.99-7.39 (m, 8H), 6.78 (d,J=7.0 Hz, 1H), 6.62 (dd, J=5.6, 2.3 Hz, 1H), 4.91 (br. s., 1H), 4.31(br. s., 1H), 3.67-3.87 (m, 2H), 3.49 (br. s., 2H), 2.26 (s, 3H), 1.88(br. s., 2H)

LR MS (ES+): 520 (M+Na⁺)

Example 92N-(2,3-dihydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 11.86 (br. s., 1H), 8.78 (s, 1H), 8.61 (s, 1H), 8.37(d, J=5.9 Hz, 1H), 7.87 (t, J=5.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.41(br. s., 1H), 7.05-7.32 (m, 7H), 6.75 (dd, J=17.7, 6.6 Hz, 2H),3.49-3.61 (m, 1H), 3.22-3.35 (m, 3H), 3.04-3.18 (m, 1H), 2.26 (s, 3H)

LR MS (ES+): 524 (M+Na⁺)

Example 93N-ethyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (DMSO-d₆) δ: 12.09 (br. s., 1H), 8.98 (s, 1H), 8.76 (s, 1H), 8.42(d, J=5.9 Hz, 1H), 7.91 (br. s., 1H), 7.45-7.65 (m, 3H), 7.05-7.38 (m,7H), 6.82-6.94 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 3.09-3.27 (m, 2H), 2.26(s, 3H), 1.06 (t, J=7.2 Hz, 3H)

LR MS (ES+): 478 (M+Na⁺)

LR MS (ES−): 454 (M−H)

Example 945-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO, 300 MHz) δ: 11.81 (br. s., 1H), 8.76 (s, 1H), 8.59 (s,1H), 8.37 (d, J=5.6 Hz, 1H), 7.55 (d, J=9.1 Hz, 2H), 7.37 (br. s., 2H),7.28 (s, 1H), 7.19-7.26 (m, 1H), 7.09-7.18 (m, 4H), 7.04 (br. s., 1H),6.78 (d, J=7.3 Hz, 2H), 6.69 (dd, J=5.4, 1.9 Hz, 1H), 2.26 (s, 3H)

LR MS (ES+): 428 (MH), 450 (M+Na⁺)

LR MS (ES−): 426 (M−H)

Example 95N-hydroxy-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO, 300 MHz): 11.98 (br. s., 1H), 10.62 (br. s., 1H), 8.87(s, 1H), 8.68 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.58 (d, J=9.1 Hz, 2H),7.04-7.46 (m, 8H), 6.80 (d, J=7.6 Hz, 2H), 2.28 (s, 3H)

LR MS (ES+): 444 (MH), 466 (M+Na⁺)

LR MS (ES−): 442 (M−H)

Example 965-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 134.

¹H NMR (d₆-DMSO, 300 MHz): 12.04 (br. s., 1H), 11.88 (br. s., 1H), 9.08(s, 1H), 8.97 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 8.25 (t, J=9.2 Hz, 1H),8.01 (d, J=7.6 Hz, 1H), 7.38 (s, 2H), 7.27 (dd, J=11.9, 2.5 Hz, 1H),6.95-7.18 (m, 3H), 6.78-6.88 (m, 1H), 6.74 (dd, J=5.6, 2.1 Hz, 1H), 2.28(s, 3H)

LR MS (ES+): 465 (MH), 487 (M+Na⁺)

LR MS (ES−): 463 (M−H)

Example 97

N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamideSimilar procedure as Example 101.

¹H NMR (d₆-DMSO, 300 MHz): 11.82 (none, 1H), 11.83 (br. s., 1H), 8.76(s, 1H), 8.60 (s, 1H), 8.37 (d, J=5.9 Hz, 1H), 7.56 (d, J=9.1 Hz, 2H),7.21-7.35 (m, 4H), 7.08-7.20 (m, 3H), 6.95 (s, 1H), 6.79 (d, J=7.0 Hz,1H), 6.66 (dd, J=5.6, 2.3 Hz, 1H), 3.37 (s, 6H), 2.28 (s, 3H)

LR MS (ES+): 526 (M+Na⁺)

LR MS (ES−): 502 (M−H)

Example 98 2-hydroxyethyl5-{4-[4-({[(4-chloro-3-(trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

¹H NMR (d₆-DMSO, 300 MHz): 12.12 (br. s., 1H), 9.19 (s, 1H), 8.97 (s,1H), 8.40 (d, J=5.9 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.53-7.70 (m, 4H),7.48 (dd, J=3.1, 1.6 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.16 (d, J=9.1 Hz,2H), 7.09 (d, J=2.3 Hz, 1H), 6.68 (dd, J=5.6, 2.3 Hz, 1H), 4.83 (t,J=5.9 Hz, 1H), 4.15 (t, J=5.0 Hz, 2H), 3.59-3.69 ppm (m, 2H)

LR MS (ES+): 583 (M+Na⁺), 585

LR MS (ES−): 559 (M−H), 561

Example 99N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-{4-[4-({[(4-chloro-3-(trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 101.

¹H NMR (d₆-DMSO, 300 MHz) 11.83 (br. s., 1H), 9.19 (s, 1H), 8.97 (s,1H), 8.37 (d, J=5.9 Hz, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.54-7.69 (m, 4H),7.23-7.31 (m, 2H), 7.12-7.19 (m, 2H), 6.93-6.97 (m, 1H), 6.67 (dd,J=5.9, 2.3 Hz, 1H), 3.37 ppm (s, 6H)

LR MS (ES−): 590 (M−H)

Example 100 methy4-(N-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxyl)-S-methylsulfonimidoyl)butanoate

LR MS (ES+): 630 (M+Na⁺)

LR MS (ES−): 606 (M−H)

Example 101N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

A mixture of5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid (60 mg, 0.13 mmol), HATU (60 mg, 0.16 mmol), sulfonimidoyldimethane(24 mg, 0.26 mmol), N,N-diisopropylethylamine (37 mg, 0.29 mmol), 200 mgof 4 Å molecular sieves and 5 ml of anhydrous 1,4-dioxane was added to athick walled reaction vessel and purged with N₂. The reaction vessel wassealed and the mixture stirred at 90° C. for 18 hours. The reactionvessel was cooled to room temperature and the mixture was poured into100 ml of water. The precipitates were filtered, washed with water anddried to give the crude, which was purified by silica gel chromatographyeluting with 3-5% MeOH/CHCl₃ to giveN-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamideas white solid. Yield: 38 mg, 54%.

¹H NMR (d₆-DMSO): 11.83 (br. s., 1H), 9.16 (s, 1H), 8.48 (br. s., 1H),8.37 (d, J=5.9 Hz, 1H), 7.98 (d, J=6.7 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H),7.26 (dd, J=8.6, 1.6 Hz, 2H), 7.05-7.19 (m, 3H), 6.96 (s, 1H), 6.75-6.85(m, 1H), 6.66 (dd, J=5.4, 1.6 Hz, 1H), 3.37 (s, 6H), 2.27 (s, 3H)

LR MS (ES+): 544 (M+Na⁺)

LR MS (ES−): 520 (M−H)

Example 102methyl(2S)-1-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)pyrrolidine-2-carboxylate

Similar procedure as Example 132.

LR MS (ES+): 623 (M+Na⁺)

LR MS (ES−): 599 (M−H)

Example 103N,N-diethyl-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.97 (br. s., 1H), 9.19 (s, 1H), 8.49 (d, J=2.6 Hz,1H), 8.40 (d, J=6.2 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.53-7.61 (m,2H), 7.40 (d, J=1.5 Hz, 1H), 7.05-7.25 (m, 4H), 7.01 (br. s., 1H),6.76-6.86 (m, 1H), 6.67-6.76 (m, 1H), 3.26-3.64 (m, 4H), 2.27 (s, 3H),1.13 (t, J=7.0 Hz, 6H)

LR MS (ES+): 524 (M+Na⁺)

LR MS (ES−): 500 (M−H)

Example 1041-(2-fluoro-5-methylphenyl)-3-{4-[(2-{4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}urea

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.87 (br. s., 1H), 9.16 (s, 1H), 8.47 (d, J=2.6 Hz,1H), 8.37 (d, J=5.6 Hz, 1H), 7.98 (dd, J=8.1, 1.9 Hz, 1H), 7.50-7.59 (m,2H), 7.35 (d, J=2.3 Hz, 1H), 7.08-7.19 (m, 4H), 6.87-6.95 (m, 1H), 6.80(ddd, J=7.7, 5.1, 2.2 Hz, 1H), 6.63 (dd, J=5.9, 2.3 Hz, 1H), 3.60 (d,J=4.1 Hz, 4H), 2.23-2.35 (m, 7H), 2.18 (s, 3H)

LR MS (ES+): 551 (M+Na⁺)

LR MS (ES−): 527 (M−H)

Example 1055-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.80 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J=2.6 Hz,1H), 8.37 (d, J=5.6 Hz, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.82 (t,J=5.7 Hz, 1H), 7.50-7.63 (m, 2H), 7.35 (dd, J=2.9, 1.8 Hz, 1H),7.00-7.20 (m, 5H), 6.80 (dt, J=7.9, 2.2 Hz, 1H), 6.70 (dd, J=5.9, 2.3Hz, 1H), 3.21-3.35 (m, 2H), 2.37-2.57 (m, 6H), 2.27 (s, 3H), 1.65 (dt,J=6.6, 3.1 Hz, 4H)

LR MS (ES+): 565 (M+Na⁺)

LR MS (ES−): 541 (M−H)

Example 1061-[4-({2-[4-(aziridin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5-methylphenyl)urea

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.90 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J=2.6 Hz,1H), 8.36 (d, J=5.9 Hz, 1H), 7.97 (dd, J=8.2, 2.1 Hz, 1H), 7.50-7.58 (m,2H), 7.28 (d, J=2.1 Hz, 1H), 7.23 (br. s., 1H), 7.04-7.17 (m, 3H), 6.97(br. s., 1H), 6.79 (ddd, J=7.5, 5.1, 2.3 Hz, 1H), 6.65 (dd, J=5.7, 2.5Hz, 1H), 4.17-4.31 (m, 2H), 3.82 (t, J=9.2 Hz, 2H), 2.26 (s, 3H)

LR MS (ES+): 494 (M+Na⁺)

LR MS (ES−): 470 (M−H)

Example 1075-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.89 (br. s., 1H), 9.21 (s, 1H), 8.50 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.98 (dd, J=8.1, 1.9 Hz, 1H), 7.53-7.62 (m,2H), 7.43 (br. s., 2H), 7.05-7.24 (m, 5H), 6.71-6.86 (m, 3H), 2.27 (s,3H)

LR MS (ES+): 468 (M+Na⁺)

LR MS (ES−): 444 (M−H)

Example 1085-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 12.10 (br. s., 1H), 10.66 (br. s., 1H), 9.29 (s, 1H),8.53 (br. s., 1H), 8.43 (d, J=6.2 Hz, 1H), 7.93-8.03 (m, 1H), 7.59 (d,J=8.8 Hz, 2H), 7.39-7.50 (m, 1H), 7.30 (br. s., 1H), 7.05-7.26 (m, 4H),6.75-6.91 (m, 2H), 2.27 (s, 3H)

LR MS (ES+): 484 (M+Na⁺)

LR MS (ES−): 460 (M−H)

Example 1091-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5-methylphenyl)urea

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.67 (br. s., 1H), 9.16 (s, 1H), 8.47 (d, J=2.1 Hz,1H), 8.34 (d, J=5.6 Hz, 1H), 7.97 (d, J=5.9 Hz, 1H), 7.54 (d, J=9.1 Hz,2H), 7.02-7.23 (m, 5H), 6.86 (br. s., 1H), 6.74-6.83 (m, 1H), 6.64 (dd,J=5.9, 2.3 Hz, 1H), 4.14-4.28 (m, 2H), 3.33-3.42 (m, 2H), 2.26 (s, 3H),1.83 (br. s., 2H)

LR MS (ES+): 486 (M+H)

LR MS (ES−): 484 (M−H)

Example 1105-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.78 (br. s., 1H), 9.20 (s, 1H), 8.51 (d, J=2.1 Hz,1H), 8.36 (d, J=5.6 Hz, 1H), 7.96 (dd, J=7.9, 1.8 Hz, 1H), 7.83 (t,J=5.7 Hz, 1H), 7.55 (d, J=9.1 Hz, 2H), 7.32-7.36 (m, 1H), 7.02-7.17 (m,5H), 6.78 (td, J=5.3, 2.6 Hz, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 4.42(t, J=5.3 Hz, 1H), 3.41 (q, J=6.2 Hz, 2H), 3.15-3.26 (m, 2H), 2.26 (s,3H), 1.60 (quin, J=6.7 Hz, 2H)

LR MS (ES+): 526 (M+Na⁺)

LR MS (ES−): 502 (M−H)

Example 111 2-(2-methoxyethoxy)ethyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J=2.3 Hz,1H), 8.38 (d, J=5.9 Hz, 1H), 7.97 (dd, J=8.1, 1.9 Hz, 1H), 7.49-7.59 (m,2H), 7.41 (dd, J=3.1, 1.6 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.03-7.17 (m,4H), 6.74-6.84 (m, 1H), 6.67 (dd, J=5.7, 2.5 Hz, 1H), 4.20-4.28 (m, 2H),3.62-3.70 (m, 2H), 3.51-3.59 (m, 2H), 3.39-3.46 (m, 2H), 3.18-3.24 (m,3H), 2.26 (s, 3H)

LR MS (ES+): 571 (M+Na⁺)

LR MS (ES−): 547 (M−H)

Example 112N-ethyl-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.93 (br. s., 1H), 9.23 (s, 1H), 8.50 (d, J=2.3 Hz,1H), 8.39 (d, J=6.2 Hz, 1H), 7.96 (dd, J=7.9, 1.8 Hz, 1H), 7.87 (t,J=5.6 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.42 (br. s., 1H), 7.02-7.27 (m,5H), 6.72-6.86 (m, 2H), 3.09-3.25 (m, 2H), 2.26 (s, 3H), 1.06 (t, J=7.2Hz, 3H)

LR MS (ES+): 496 (M+Na⁺)

LR MS (ES−): 472 (M−H)

Example 113 2-methoxyethyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.15 (s, 1H), 8.46 (br. s., 1H),8.38 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.41 (d,J=1.2 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.01-7.19 (m, 4H), 6.78 (d, J=5.9Hz, 1H), 6.66 (dd, J=5.9, 2.1 Hz, 1H), 4.17-4.32 (m, 2H), 3.51-3.65 (m,2H), 3.29 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 527 (M+Na⁺)

LR MS (ES−): 503 (M−H)

Example 1145-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-methoxyethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.86 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J=2.3 Hz,1H), 8.38 (d, J=5.9 Hz, 1H), 7.86-8.02 (m, 2H), 7.56 (d, J=8.8 Hz, 2H),7.40 (br. s., 1H), 7.02-7.21 (m, 5H), 6.67-6.84 (m, 2H), 3.26-3.50 (m,7H), 2.26 (s, 3H)

LR MS (ES+): 526 (M+Na⁺)

LR MS (ES−): 502 (M−H)

Example 1155-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 134.

¹H NMR (d₆-DMSO): 12.05 (br. s., 1H), 8.79 (s, 1H), 8.62 (s, 1H), 8.39(d, J=5.6 Hz, 1H), 7.52-7.61 (m, 2H), 7.39 (dd, J=3.1, 1.6 Hz, 1H), 7.34(d, J=2.3 Hz, 1H), 7.30 (s, 1H), 7.21-7.27 (m, 1H), 7.10-7.20 (m, 3H),7.05 (s, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.68 (dd, J=5.6, 2.3 Hz, 1H), 2.28(s, 3H)

LR MS (ES−): 427 (M−H)

Example 116 methyl5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.02 (br. s., 1H), 8.85 (br. s.,1H), 8.36 (d, J=5.6 Hz, 1H), 7.50-7.59 (m, 2H), 7.41 (d, J=1.5 Hz, 1H),7.33 (d, J=2.3 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.08-7.18(m, 3H), 7.06 (d, J=1.5 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.65 (dd,J=5.6, 2.3 Hz, 1H), 3.69 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 465 (M+Na⁺)

LR MS (ES−): 441 (M−H)

Example 1175-{4-[2-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 134.

¹H NMR (d₆-DMSO): 12.03 (br. s., 1H), 11.86 (br. s., 1H), 9.62 (s, 1H),8.65 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 7.94 (dd, J=7.9, 1.8 Hz, 1H), 7.72(dd, J=13.2, 2.3 Hz, 1H), 7.26-7.40 (m, 3H), 7.15-7.24 (m, 1H),7.01-7.14 (m, 2H), 6.81 (td, J=5.3, 2.3 Hz, 1H), 6.68 (dd, J=5.7, 2.2Hz, 1H), 2.26 (s, 3H)

LR MS (ES+): 487 (M+Na⁺)

LR MS (ES−): 463 (M−H)

Example 118 methyl5-{4-[2-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

¹H NMR (d₆-DMSO): 12.13 (br. s., 1H), 9.34 (s, 1H), 8.55 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.94 (dd, J=7.8, 1.6 Hz, 1H), 7.72 (dd,J=13.5, 2.3 Hz, 1H), 7.43 (dd, J=3.2, 1.8 Hz, 1H), 7.37 (d, J=2.3 Hz,1H), 7.26-7.36 (m, 1H), 7.18 (dd, J=8.9, 1.6 Hz, 1H), 7.05-7.15 (m, 2H),6.77-6.87 (m, 1H), 6.70 (dd, J=5.6, 2.3 Hz, 1H), 3.70 (s, 3H), 2.26 (s,3H)

LR MS (ES+): 501 (M+Na⁺)

LR MS (ES−): 477 (M−H)

Example 1195-(4-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 135

¹H NMR (d₆-DMSO),12.12 (br.s., 1H), 9.04 (s,1 9.11 (s, 1H), 8.96 (s,1H), 8.38 (d, J=5.6 Hz, 1H), 7.99 (dd, J=6.4, 2.3 Hz, 1H), 7.60-7.72 (m,1H), 7.56 (d, J=9.1 Hz, 2H), 7.27-7.49 (m, 3H), 7.14 (d, J=9.1 Hz, 2H),7.03 (br. s., 1H), 6.67 (dd, J=5.7, 2.2 Hz, 1H)

LR MS (ES−): 499 (M−H)

Example 120 methyl5-(4-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.04 (s, 1H), 8.91 (s, 1H), 8.37(d, J=6.2 Hz, 1H), 7.99 (dd, J=6.4, 2.6 Hz, 1H), 7.60-7.69 (m, 1H),7.51-7.61 (m, 2H), 7.37-7.49 (m, 2H), 7.34 (d, J=2.1 Hz, 1H), 7.09-7.18(m, 2H), 7.01-7.09 (m, 1H), 6.66 (dd, J=5.6, 2.3 Hz, 1H), 3.70 (s, 3H)

LR MS (ES+): 537 (M+Na⁺)

LR MS (ES−): 513 (M−H)

Example 1215-(4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid

Similar procedure as Example 134.

¹H NMR (d₆-DMSO): 12.08 (br. s., 1H), 9.23 (s, 1H), 9.00 (s, 1H), 8.39(d, J=5.6 Hz, 1H), 8.10 (s, 1H), 7.48-7.72 (m, 4H), 7.27-7.47 (m, 2H),7.00-7.23 (m, 3H), 6.69 (br. s., 1H)

LR MS (ES−): 515 (M−H)

Example 122 methyl5-(4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.38(d, J=5.9 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.51-7.69 (m, 4H), 7.42 (dd,J=3.2, 1.8 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.10-7.18 (m, 2H), 7.03-7.09(m, 1H), 6.66 (dd, J=5.9, 2.3 Hz, 1H), 3.70 (s, 3H)

LR MS (ES+): 553 (M+Na⁺)

LR MS (ES−): 529 (M−H)

Example 1234-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylicacid

To a stirred solution of methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate(550 mg, 1.15 mmol) in a mixture of solvents—THF/MeOH (20 ml/20 ml) wasadded 1 ml of 5M NaOH (5 mmol) solution. The mixture was heated in a 66°C. bath for 2 hours, cooled to room temperature and poured into 200 mlof water. 2M HCl was added until pH=5. The resulting precipitates werefiltered, washed with water, and dried in vacuo to give4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylicacid as off-white solid. Yield: 520 mg, 97%.

¹H NMR (d₆-DMSO): 9.30 (s, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.43 (d, J=5.9Hz, 1H), 8.35 (br. s., 1H), 8.13 (br. s., 1H), 7.95 (dd, J=7.8, 1.9 Hz,1H), 7.51-7.59 (m, 2H), 7.45 (s, 1H), 7.03-7.18 (m, 3H), 6.75-6.83 (m,1H), 6.72 (dd, J=5.6, 2.3 Hz, 1H), 2.25 (s, 3H)

LR MS (ES−): 462 (M−H)

Example 124 2-hydroxyethyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate

¹H NMR (DMSO-d₆) δ: 12.11 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J=2.1 Hz,1H), 8.33 (d, J=5.6 Hz, 1H), 7.97 (dd, J=7.9, 1.8 Hz, 1H), 7.63 (dd,J=2.9, 1.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.22-7.37 (m, 2H), 7.01-7.18(m, 3H), 6.72-6.85 (m, 1H), 6.58 (dd, J=5.6, 2.3 Hz, 1H), 4.83 (t, J=5.9Hz, 1H), 4.19 (t, J=5.1 Hz, 2H), 3.57-3.73 (m, 2H), 2.25 (s, 3H)

LR MS (ES+): 491 (MH), 513 (M+Na⁺)

LR MS (ES−): 489 (M−H)

Example 125{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}aceticacid

To a stirred solution of methyl{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetate(50 mg, 0.085 mmol) in THF/MeOH (5 ml/5 ml) was added IM NaOH solution(3 ml, 3 mmol). The mixture was stirred at room temperature for onehour, and poured into 50 ml of water. 2M HCl was added until pH=4. Theresulting precipitates were filtered, washed with water, and dried invacuo to give{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}aceticacid as white solid. Yield: 47 mg, 96%.

LR MS (ES−): 570 (M−H)

Example 126 methyl{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetate

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.83 (br. s., 1H), 9.14 (s, 1H), 8.46 (br. s., 1H),8.35 (d, J=5.6 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H),7.33 (d, J=1.8 Hz, 1H), 7.01-7.18 (m, 4H), 6.86 (s, 1H), 6.80 (d, J=4.4Hz, 1H), 6.61 (dd, J=5.9, 2.1 Hz, 1H), 4.26 (br. s., 2H), 3.57 (s, 3H),2.87 (br. s., 2H), 2.18-2.32 (m, 5H), 1.93 (br. s., 1H), 1.65 (br. s.,2H), 1.14 (br. s., 2H)

LR MS (ES+): 608 (M+Na⁺)

LR MS (ES−): 584 (M−H)

Example 127N-(2,3-dihydroxypropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.81 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J=2.3 Hz,1H), 8.36 (d, J=5.6 Hz, 1H), 7.97 (dd, J=7.8, 1.9 Hz, 1H), 7.86 (t,J=5.7 Hz, 1H), 7.51-7.60 (m, 2H), 7.38 (dd, J=3.1, 1.6 Hz, 1H),7.10-7.19 (m, 3H), 7.07 (td, J=4.3, 2.5 Hz, 2H), 6.74-6.84 (m, 1H), 6.69(dd, J=5.6, 2.3 Hz, 1H), 4.78 (d, J=5.0 Hz, 1H), 4.54 (t, J=5.9 Hz, 1H),3.48-3.60 (m, 1H), 3.23-3.36 (m, 3H), 3.05-3.18 (m, 1H), 2.26 (s, 3H)

LR MS (ES+): 542 (M+Na⁺)

LR MS (ES−): 518 (M−H)

Example 1285-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.79 (br. s., 1H), 9.30 (s, 1H), 8.57 (d, J=1.5 Hz,1H), 8.36 (d, J=5.6 Hz, 1H), 7.95 (dd, J=7.9, 1.8 Hz, 1H), 7.84 (t,J=5.6 Hz, 1H), 7.50-7.63 (m, 2H), 7.35 (d, J=1.5 Hz, 1H), 7.00-7.21 (m,5H), 6.79 (td, J=5.3, 2.5 Hz, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 4.66(t, J=5.6 Hz, 1H), 3.38-3.51 (m, 2H), 3.22 (q, J=6.1 Hz, 2H), 2.25 (s,3H)

LR MS (ES+): 512 (M+Na⁺)

LR MS (ES−): 488 (M−H)

Example 1291-(2-fluoro-5-methylphenyl)-3-{4-[(2-{4-[(4-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}urea

Similar procedure as Example 132.

¹H NMR (d₆-DMSO): 11.84 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J=2.3 Hz,1H), 8.37 (d, J=5.6 Hz, 1H), 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.55 (d,J=8.8 Hz, 2H), 7.36 (d, J=2.3 Hz, 1H), 7.04-7.20 (m, 4H), 6.89 (s, 1H),6.81 (td, J=5.3, 2.3 Hz, 1H), 6.63 (dd, J=5.9, 2.3 Hz, 1H), 4.73 (d,J=4.1 Hz, 1H), 3.90-4.06 (m, 2H), 3.71 (dt, J=8.4, 4.3 Hz, 1H), 3.25 (d,J=2.6 Hz, 2H), 2.27 (s, 3H), 1.73 (d, J=4.1 Hz, 2H), 1.21-1.44 (m, 2H)

LR MS (ES+): 552 (M+Na⁺)

LR MS (ES−): 528 (M−H)

Example 130 2,3-dihydroxypropyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.24 (s, 1H), 8.54 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.51-7.62 (m,2H), 7.48 (dd, J=3.1, 1.6 Hz, 1H), 7.34-7.40 (m, 1H), 7.05-7.20 (m, 4H),6.75-6.87 (m, 1H), 6.68 (dd, J=5.9, 2.3 Hz, 1H), 4.92 (d, J=5.3 Hz, 1H),4.64 (t, J=5.7 Hz, 1H), 4.11-4.22 (m, 1H), 3.97-4.09 (m, 1H), 3.67-3.79(m, 1H), 3.38-3.46 (m, 2H), 2.28 (s, 3H)

LR MS (ES+): 543 (M+Na⁺)

LR MS (ES−): 519 (M−H)

Example 131 2-hydroxyethyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

A mixture of5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid (50 mg, 0.11 mmol), ethylene glycol (1 ml),1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl,25 mg, 0.13 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) inanhydrous THF (10 ml) was stirred at 60° C. for 16 hours. The mixturewas poured into 100 ml of water. 2M HCl was added dropwise until pH=4.The precipitates were filtered, washed with water and dried in vacuo togive the crude, which was purified by silica gel chromatography with agradient of 3-5% MeOH/CHCl₃ to give 2-hydroxyethyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylateas white solid. Yield: 36 mg, 67%.

¹H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J=1.8 Hz,1H), 8.39 (d, J=5.6 Hz, 1H), 7.94-8.05 (m, 1H), 7.56 (d, J=9.1 Hz, 2H),7.48 (d, J=1.5 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.03-7.23 (m, 4H),6.75-6.86 (m, 1H), 6.69 (dd, J=5.7, 2.2 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H),4.15 (t, J=5.1 Hz, 2H), 3.64 (q, J=5.4 Hz, 2H), 2.27 (s, 3H)

LR MS (ES+): 513 (M+Na⁺)

LR MS (ES−): 489 (M−H)

Example 1321-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea

A mixture of5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid (50 mg, 0.1 mmol), HATU (51 mg, 0.13 mmol) andN,N-diisopropylethylamine (31 mg, 0.24 mmol) in anhydrous DMF (10 ml)was stirred at room temperature for 10 minutes, followed by addition of(R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred foranother 10 minutes and poured into 100 ml of water. 2M HCl was addeddropwise until pH=4˜5. The precipitates were filtered, washed with waterand dried in vacuo to give1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)ureaas white solid. Yield: 40 mg, 71%.

¹H NMR (d₆-DMSO): 11.90 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J=2.6 Hz,1H), 8.38 (d, J=5.9 Hz, 1H), 7.99 (dd, J=7.8, 1.9 Hz, 1H), 7.51-7.62 (m,2H), 7.37 (d, J=2.3 Hz, 1H), 7.25 (br. s., 1H), 7.02-7.19 (m, 4H),6.76-6.86 (m, 1H), 6.64 (dd, J=5.6, 2.3 Hz, 1H), 4.93 (br. s., 1H),4.22-4.38 (m, 1H), 3.69-3.87 (m, 1H), 3.43-3.59 (m, 2H), 3.35-3.42 (m,1H), 2.27 (s, 3H), 1.90 (br. s., 2H)

LR MS (ES+): 538 (M+Na⁺)

LR MS (ES−): 514 (M−H)

Example 1331-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea

Similar procedure as Example 132.

LR MS (ES+): 538 (M+Na⁺)

LR MS (ES−): 514 (M−H)

Example 1345-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid

To a stirred solution of methyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate(1.38 g, 3.00 mmol) in a mixture of solvents THF/MeOH (20 ml/20 ml) wasadded 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a72° C. bath for 5 hours, cooled to room temperature and poured into 200ml of water. 2M HCl was added until pH=3. The resulting precipitateswere filtered, washed with water, and dried in vacuo to give5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid as light brown solid. Yield: 1.28 g, 96%.

¹H NMR (d₆-DMSO): 12.04 (br. s., 1H), 11.88 (br. s., 1H), 9.18 (s, 1H),8.49 (d, J=2.3 Hz, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.94-8.05 (m, 1H), 7.56(d, J=9.1 Hz, 2H), 7.31-7.42 (m, 2H), 7.01-7.21 (m, 4H), 6.81 (td,J=5.2, 2.2 Hz, 1H), 6.68 (dd, J=5.6, 2.3 Hz, 1H), 2.27 (s, 3H)

LR MS (ES−): 467 (M−H)

Example 135 methyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

To a stirred solution of methyl5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0 g, 3.23mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (488 mg, 3.23 mmol). The mixture wasstirred at room temperature for one hour and poured into 200 ml of 0.02MHCl solution with vigorous stirring. The resulting precipitates werefiltered, washed with water, and dried in vacuo to give methyl5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylateas white solid. Yield: 1.38 g, 93%.

¹H NMR (d₆-DMSO): 12.14 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J=2.3 Hz,1H), 8.39 (d, J=5.9 Hz, 1H), 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.53-7.59 (m,2H), 7.44 (dd, J=3.2, 1.5 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.06-7.18 (m,4H), 6.77-6.85 (m, 1H), 6.68 (dd, J=5.6, 2.3 Hz, 1H), 3.72 (s, 3H), 2.28(s, 3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES−): 459 (M−H)

Preparation of 1-tert-butyl 2-methyl4-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate

Similar procedure as 1-tert-butyl 2-methyl4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate.

¹H NMR (d₆-DMSO): 8.38 (d, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.45 (d, J=2.1Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 6.67 (dd,J=5.7, 2.2 Hz, 1H), 6.43 (d, J=7.9 Hz, 1H), 6.20-6.33 (m, 2H), 5.32 (br.s., 2H), 3.72-3.85 (m, 3H), 1.53 (s, 9H)

LR MS (ES+): 432 (M+Na⁺)

Example 136 methyl4-{4-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate

To a stirred solution of 1-tert-butyl 2-methyl4-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate (150 mg,0.37 mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (67 mg, 0.44 mmol). The mixture wasstirred at room temperature for 3 hours and poured into 100 ml of water.The resulting precipitates were filtered, washed with water, and driedin vacuo to give the Boc-protected intermediate as brown solid. Thisintermediate was dissolved in 5 ml of methylene chloride, and 3 ml oftrifluoroacetic acid was added. Stirring was continued for 20 minutes.The mixture was evaporated to dryness to give the crude product, whichwas purified by silica gel chromatography eluting with 5% MeOH/CHCl₃ togive methyl4-{4-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylateas white solid. Yield: 67 mg, 39%.

¹H NMR (d₆-DMSO): 12.18 (br. s., 1H), 9.23 (s, 1H), 8.47 (br. s., 1H),8.36 (d, J=5.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.63 (br. s., 1H),7.25-7.47 (m, 4H), 7.16 (d, J=7.9 Hz, 1H), 7.07 (dd, J=11.4, 8.5 Hz,1H), 6.72-6.85 (m, 2H), 6.65 (dd, J=5.6, 2.1 Hz, 1H), 3.76 (s, 3H), 2.22(s, 3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES−): 459 (M−H)

Example 137N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide

Similar procedure as Example 101.

LR MS (ES+): 544 (M+Na⁺)

LR MS (ES−): 520 (M−H)

Example 1384-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N,N-dimethyl-1H-pyrrole-2-carboxamide

The title compound was isolated as a side product in the synthesis ofExample 137.

LR MS (ES+): 474 (M+H)

LR MS (ES−): 472 (M−H

Example 1394-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-methyl-1H-pyrrole-2-carboxamide

A mixture of4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylicacid (50 mg, 0.1 mmol), HATU (50 mg, 0.13 mmol), 2M methylamine/THFsolution (0.1 ml, 0.2 mmol) and N,N-diisopropylethylamine (31 mg, 0.24mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10minutes. The mixture was poured into 100 ml of water. The precipitateswere filtered, washed with water and dried to give the crude, which waspurified by silica gel chromatography with 3-5% MeOH/CHCl₃ to give4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-methyl-1H-pyrrole-2-carboxamideas white solid. Yield: 21 mg, 41%.

¹H NMR (d₆-DMSO): 11.69 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J=2.3 Hz,1H), 8.32 (d, J=5.6 Hz, 1H), 8.01-8.12 (m, 1H), 7.96 (dd, J=7.8, 1.9 Hz,1H), 7.48-7.61 (m, 2H), 7.43 (dd, J=2.9, 1.5 Hz, 1H), 7.03-7.23 (m, 5H),6.79 (dt, J=8.1, 2.3 Hz, 1H), 6.61 (dd, J=5.6, 2.3 Hz, 1H), 2.71 (d,J=4.7 Hz, 3H), 2.26 (s, 3H)

LR MS (ES+): 482 (M+Na⁺)

LR MS (ES−): 458 (M−H)

Preparation of 4-(4-aminophenoxy)-6-chloropyridin-2-amine

A stirred solution of 4-aminophenol (335 mg, 3.1 mmol) in anhydrous DMSO(8 ml) was flushed with nitrogen and treated with 1M KOBu^(t)/THFsolution (3.1 ml, 3.1 mmol). The mixture was stirred at room temperatureunder nitrogen for 10 minutes. 4,6-dichloropyridin-2-ylamine (500 mg,3.1 mmol) was added and the mixture was heated at 88° C. for 16 hours,cooled to room temperature and poured into 100 ml of water. Theresulting precipitates were filtered, washed with water and dried togive the crude product, which was purified by silica gel chromatographywith 2˜5% MeOH/CHCl₃ to give 4-(4-aminophenoxy)-6-chloropyridin-2-amineas light brown solid. Yield: 350 mg, 49%.

Example 140 1-tert-butyl 2-methyl4-{6-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-1,2-dicarboxylate

Similar procedure as Example 148.

LR MS (ES+): 598 (M+Na⁺)

Example 1411-(4-{[2-amino-6-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-(2-fluoro-5-methylphenyl)urea

Similar procedure as Example 148.

¹H NMR (d₆-DMSO): 11.02 (br. s., 1H), 9.11 (s, 1H), 8.44 (br. s., 1H),7.97 (d, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.98-7.17 (m, 3H), 6.78 (br. s.,2H), 6.53 (br. s., 2H), 6.05 (br. s., 1H), 5.74 (br. s., 2H), 5.61 (s,1H), 2.25 (s, 3H)

LR MS (ES+): 418 (M+H)

LR MS (ES−): 416 (M−H)

Example 1424-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylicacid

To a stirred solution of methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate(220 mg, 0.48 mmol) in THF/MeOH (3 ml/10 ml) was added IM NaOH (4.0 ml,4.0 mmol). The mixture was heated at 70° C. for 2 hours, cooled to roomtemperature and poured into 100 ml of water. 1M HCl was added until pH=4and the resulting precipitates were filtered, washed with water anddried in vacuo to give4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylicacid.

Yield: 200 mg, 94%.

¹H NMR (d₆-DMSO): 12.38 (br. s., 1H), 12.04 (br. s., 1H), 9.14-9.23 (m,1H), 8.48 (d, J=2.3 Hz, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.97 (dd, J=7.9,2.1 Hz, 1H), 7.60 (br. s., 1H), 7.50-7.58 (m, 2H), 7.30 (d, J=2.1 Hz,1H), 7.22 (s, 1H), 7.03-7.18 (m, 3H), 6.73-6.84 (m, 1H), 6.60 (dd,J=5.6, 2.3 Hz, 1H), 2.25 (s, 3H)

LR MS (ES−): 445 (M−H)

Preparation of 1-tert-butyl 2-methyl4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate

A 100 ml flask was charged with 4-((2-chloropyridin-4-yl)oxy)aniline(150 mg, 0.68 mmol), 1-tert-butyl 2-methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate(260 mg, 0.8 mmol), 2M Na₂CO₃ solution (0.5 ml, 1.0 mmol),PdCl₂(PPh₃)₂(5 mg, 0.007 mmol), 10 ml of 1,4-dioxane and 3 ml of water.The mixture was flushed with nitrogen and heated at 70° C. for 30minutes. The mixture was cooled to room temperature and poured into 100ml of water. The precipitates were filtered and dried to give the crude,which was further purified by silica gel chromatography eluting with2-3% MeOH/CHCl₃ to give 1-tert-butyl 2-methyl4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate as lightbrown oil.

Yield: 240 mg, 86%.

Example 143 Methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate

To a stirred solution of 1-tert-butyl 2-methyl4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate (240 mg,0.59 mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (107 mg, 0.71 mmol). The mixture wasstirred at room temperature for 30 minutes and poured into 100 ml ofwater. The resulting precipitates were filtered, washed with water anddried to give a brown oil. Purification by silica gel chromatographyeluting with 2-3% MeOH/CHCl₃ gave the Boc-protected intermediate aslight green oil, which was dissolved in 5 ml of methylene chloride,followed by addition of 3 ml of trifluoroacetic acid. The mixture wasstirred at room temperature for 10 minutes, evaporated to dryness, andpurified by silica gel chromatography eluting with 2-5% MeOH/CHCl₃ togive methyl4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylateas white solid. Yield: 135 mg, 50%.

¹H NMR (d₆-DMSO): 12.17 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J=2.3 Hz,1H), 8.33 (d, J=5.9 Hz, 1H), 7.91-8.04 (m, 1H), 7.61 (dd, J=3.1, 1.6 Hz,1H), 7.53 (d, J=9.1 Hz, 2H), 7.22-7.31 (m, 2H), 7.02-7.17 (m, 3H),6.73-6.85 (m, 1H), 6.58 (dd, J=5.7, 2.5 Hz, 1H), 3.76 (s, 3H), 2.26 (s,3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES−): 459 (M−H)

Preparation of tert-butyl2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate

To a stirred mixture of N-Boc-pyrrole-2-boronic acid (114 mg, 0.54 mmol)and 4-((2-chloropyridin-4-yl)oxy)aniline (100 mg, 0.45 mmol) in 8 ml of1,4-dioxane, was added PdCl₂(PPh₃)₂(10 mg, 0.014 mmol) and IM Na₂CO₃aqueous solution (0.5 ml, 1.0 mmol). The mixture was heated at 72° C.under N₂ for one hour, cooled to room temperature and poured into 100 mlof water. The resulting mixture was extracted with EtOAc (2×50 ml). Theorganic layers were combined, washed with brine (50 ml), dried overNa₂SO₄, and evaporated to give a brown oil, which was purified by silicagel chromatography with a gradient of 20-50% EtOAc/hexanes to givetert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylateas colorless oil.

Yield: 110 mg, 70%.

Example 1441-(2-fluoro-5-methylphenyl)-3-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea

To a stirred solution of tert-butyl2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate (100 mg,0.28 mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (51 mg, 0.34 mmol). The mixture wasstirred at room temperature for one hour and poured into 100 ml ofwater. The resulting mixture was extracted with EtOAc (2×50 ml). Theorganic layers were combined, washed with brine (50 ml), dried overNa₂SO₄, and evaporated to give a brown oil, which was purified by silicagel chromatography with 2-5% MeOH/CHCl₃ to give the Boc-protectedintermediate as light green oil. The oil was dissolved in 5 ml ofmethylene chloride, and 3 ml of trifluoroacetic acid was added. Stirringwas continued for 10 hours, and the mixture was evaporated to dryness.The brown residue was dissolved in methanol (5 ml). This methanolsolution was then added dropwise into 100 ml of IM NaHCO₃ solution withstirring. The resulting precipitates were filtered, washed with water,and dried in vacuo to give1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)ureaas light grey solid.

¹H NMR (d₆-DMSO): 11.43 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J=2.6 Hz,1H), 8.32 (d, J=5.6 Hz, 1H), 7.96 (dd, J=7.9, 1.8 Hz, 1H), 7.48-7.58 (m,2H), 7.20 (d, J=2.1 Hz, 1H), 7.04-7.16 (m, 3H), 6.75-6.86 (m, 2H), 6.67(dt, J=3.8, 1.9 Hz, 1H), 6.57 (dd, J=5.9, 2.3 Hz, 1H), 6.05-6.13 (m,1H), 2.25 (s, 3H)

Example 145 1-phenyl-3-{4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]phenyl}urea

Similar procedure as Example 148.

¹H NMR (DMSO-d₆) δ: 11.46 (br. s., 1H), 8.79 (s, 1H), 8.75 (d, J=1.8 Hz,1H), 8.67 (s, 1H), 7.98 (dd, J=8.4, 2.5 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H),7.67 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.45 (d, J=7.6 Hz, 2H),7.27 (t, J=7.9 Hz, 2H), 6.96 (t, J=7.3 Hz, 1H), 6.84-6.88 (m, 1H), 6.77(t, J=3.8 Hz, 1H), 6.11-6.16 (m, 1H)

Example 1461-(2-fluoro-5-methylphenyl)-3-{3-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea

Similar procedure as Example 148.

LR MS (ES+): 387 (M+H⁺)

Example 1471-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-3-yl)pyridin-4-yl]phenyl}urea

Similar procedure as Example 148.

¹H NMR (d₆-DMSO): 11.72 (br. s., 1H), 9.49 (br. s., 1H), 8.63 (s, 1H),8.53 (d, J=6.4 Hz, 1H), 8.38 (br. s., 1H), 8.07 (d, J=8.5 Hz, 2H),8.00-8.04 (m, 1H), 7.97 (dd, J=7.9, 1.8 Hz, 1H), 7.81-7.90 (m, 1H), 7.69(d, J=8.8 Hz, 2H), 7.13 (dd, J=11.3, 8.4 Hz, 1H), 7.03 (d, J=2.1 Hz,1H), 6.98 (br. s., 1H), 6.84 (ddd, J=7.8, 5.3, 2.1 Hz, 1H), 2.21-2.36(m, 3H)

LR MS (ES+): 387 (M+H)

tert-butyl(4-(2-chloropyridin-4-yl)phenyl)carbamate

To a mixture of (4-boc-aminophenyl)boronic acid (200 mg, 0.84 mmol) and2-chloro-4-bromopyridine (162 mg, 0.84 mmol) in 10 ml of 1,4-dioxane,was added PdCl₂(PPh₃)₂(10 mg, 0.014 mmol) and IM Na₂CO₃ aqueous solution(0.5 ml, 1.0 mmol). The mixture was heated at 70° C. under N₂ for 2hours, cooled to room temperature and poured into 100 ml of water. Thebrown precipitates were filtered, washed with water and dried to givetert-butyl(4-(2-chloropyridin-4-yl)phenyl)carbamate as the crudeproduct.

4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline

To a mixture of N-Boc-pyrrole-2-boronic acid (210 mg, 1.0 mmol) andtert-butyl(4-(2-chloropyridin-4-yl)phenyl)carbamate (250 mg, 0.82 mmol)in 10 ml of 1,4-dioxane, was added PdCl₂(PPh₃)₂(10 mg, 0.014 mmol) andIM Na₂CO₃ aqueous solution (0.75 ml, 1.5 mmol). The mixture was heatedat 60° C. under N₂ for 3 hours, cooled to room temperature and pouredinto 100 ml of water. The precipitates were filtered, dried and purifiedby silica gel chromatography with 1-5% MeOH/CHCl₃ to give theintermediate as light yellow oil. This intermediate was dissolved in 10ml of methylene chloride and 3 ml of trifluoroacetic acid was added. Themixture was stirred at room temperature for 16 hours and evaporated todryness to give 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline TFA salt aslight brown solid. Yield: 290 mg, 100%.

Example 1481-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea

To a stirred suspension of 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline TFAsalt (60 mg, 0.17 mmol) in anhydrous THF (10 ml) was added2-fluoro-5-methyl-phenylisocyanate (48 mg, 0.32 mmol) andN,N-diisopropylethylamine (40 mg, 0.31 mmol). After 1 hour, the reactionmixture was evaporated and purified by silica gel chromatography with2-3% MeOH/CHCl₃ to give1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}ureaas off-white solid. Yield: 28 mg.

¹H NMR (d₆-DMSO): 11.49 (br. s., 1H), 9.29 (br. s., 1H), 8.52-8.60 (m,1H), 8.48 (d, J=5.3 Hz, 1H), 7.94-8.04 (m, 2H), 7.84 (d, J=8.5 Hz, 2H),7.62 (d, J=8.5 Hz, 2H), 7.42 (dd, J=5.3, 1.5 Hz, 1H), 7.12 (dd, J=11.4,8.2 Hz, 1H), 6.89 (s, 2H), 6.82 (dt, J=5.4, 2.6 Hz, 1H), 6.16 (t, J=2.9Hz, 1H), 2.29 (s, 3H)

LR MS (ES+): 409 (M+Na⁺)

LR MS (ES−): 385 (M−H)

3.2 Biological Testing

Biological data for the compounds of the present invention was generatedby the use of one or more of the following assays.

VEGF Stimulated Ca.sup.++Signal in Vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of VEGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. HUVEC (humanumbilical vein endothelial cells) (Clonetics) were seeded in 96-wellfibronectin coated black-walled plates overnight at 37.degree. C./5%CO.sub.2. Cells were loaded with calcium indicator Fluo-4 for 45 minutesat 37.degree. C. Cells were washed 4 times (Original Cell Wash,Labsystems) to remove extracellular dye. Test compounds werereconstituted in 100% DMSO and added to the cells to give a final DMSOconcentration of 0.1%. For screening, cells were pre-incubated with testagents for 30 minutes, at a single concentration (10.mu.M) or atconcentrations ranging from 0.01 to 10.0.mu.M followed by VEGFstimulation (5 ng/mL). Changes in fluorescence at 516 nm were measuredsimultaneously in all 96 wells using a cooled CCD camera. Data weregenerated by determining max-min fluorescence levels for unstimulated,stimulated, and drug treated samples. IC.sub.50 values for testcompounds were calculated from % inhibition of VEGF stimulated responsesin the absence of inhibitor.

VEGFR² Kinase Assay

The cytoplasmic domain of the human VEGF receptor (VEGFR-2) wasexpressed as a Histidine-tagged fusion protein following infection ofinsect cells using an His engineered baculovirus. His-VEGFR-2 waspurified to homogeneity, as determined by SDS-PAGE, using nickel resinchromatography. Kinase assays were performed in 96 well microtiterplates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates wereincubated with 1% BSA and then washed four times with PBS prior tostarting the reaction. Reactions were carried out in 120.mu.L reactionvolumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4).Test compounds were reconstituted in 100% DMSO and added to the reactionto give a final DMSO concentration of 5%. Reactions were initiated bythe addition 0.5 ng of purified protein. Following a ten minuteincubation at 25.degree. C., the reactions were washed four times withPBS containing 0.05% Tween-20. 100.mu.1 of a monoclonalanti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000in PBS-Tween-20 and added to the wells for 30 minutes. Following fourwashes with PBS-Tween-20, 100.mu.l of O-phenylenediamine Dihydrochloridein Phosphate-citrate buffer, containing urea hydrogen peroxide, wasadded to the wells for 7 minutes as a colorimetric substrate for theperoxidase. The reaction was terminated by the addition of 100.mu.l of2.5N H.sub.2 SO.sub.4 to each well and read using a microplate ELISAreader set at 492 nm. IC.sub.50 values for compound inhibition werecalculated directly from graphs of optical density (arbitrary units)versus compound concentration following subtraction of blank values.Compounds of the current invention have the IC50 value in the range of0.01 to 500 nM.

VEGF-Induced Dermal Extravasation in Guinea Pig (Miles Assay)

Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane,sheared, and given a single dose of drug or the respective vehicle. Theguinea pigs were dosed orally unless indicated otherwise in Table 3. Tenminutes prior to the end of drug treatment, guinea pigs wereanesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS(13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes,triplicate intradermal injections of 100 ng rhVEGF.sub. 165 in 100.mu.1PBS and of 100.mu.1 PBS alone were administered on the flank. After 20minutes, each animal was cuthanized with Pentosol, and the skincontaining the intradermal injection sites was removed for imageanalysis.

Using an analog video camera coupled to a PC, an image of eachtrans-illuminated skin sample was captured, and the integrated opticaldensity of each injection site was measured using ImagePro 4. For eachskin sample, the difference between the mean optical density of the VEGFsites and mean optical density of the PBS sites is the measure ofVEGF-induced EBD extravasation in that animal. These measured valueswere averaged per study group to determine the mean VEGF-induced EBDextravasation for each experimental condition, and the group means werethen compared to assess inhibition of VEGF-induced EBD extravasation inthe drug-treated groups relative to the vehicle-treated controls.

To determine the dose required for 50% inhibition (ID.sub.50), thepercent inhibition data was plotted as a function of oral dose, usingthe ‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50value was verified visually by using the plotted data (horizontal linefrom 50% y value, at intersection with best-fit line drop vertical lineto x axis (dose).

Laser-Induced Choroidal Neovascularization (CNV) in Rat (CNV Assay).

CNV was induced and quantified in this model as previously described(Edelman and Castro. Exp. Eye Res. 2000; 71:523-533). On day 0, maleBrown Norway rats (200-300 g) were anesthetized with 100 mg/kg Ketamineand 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide.Using the blue-green setting of a Coherent Novus Argon Laser, 3 laserburns (90 mW for 0.1 s; 100.mu.m diameter) were given to each eyebetween the retinal vessels around the optic nerve head. Rats were dosedwith test compounds in their indicated vehicles orally once daily.

On day 10, rats were sacrificed with 100% CO.sub.2, and blood vesselswere labeled by vascular perfusion with 10 mg/ml FITC-dextran (MW2.times. 10.sup.6). Using an epifluorescence microscope (20.times.)coupled to a spot digital camera and a PC, images were obtained from theflat mounts of the RPE-choroid-sclera from each eye, and the areaoccupied by hyperfluorescent neovessels within each laser lesion wasmeasured using ImagePro 4 software.

To determine the dose required for 50% inhibition (ID.sub.50), thepercent inhibition data was plotted as a function of oral dose, usingthe ‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50value was verified visually by using the plotted data (horizontal linefrom 50% y value, at intersection with best-fit line drop vertical lineto x axis (dose).

The foregoing description can be employed to practice the presentinvention, and represents the best mode contemplated. It should not beconstrued as limiting the overall scope hereof.

Rabbit Eye VEGF Permeability Model

Assay used was detailed by Jeffrey Edelman, etc in Exp. Eye. Res.80(2005), Pg 249-258.

PDGF Stimulated Ca²⁺ Signal in Vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of PDGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad(Normal human dermal fibroblasts) (Lonza) were seeded in 384-wellfibronectin coated black-walled plates overnight at 37° C./5% CO₂. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 4 times (ELx405-CW, Bio-Tek) to remove extracellular dye.Test compounds were reconstituted in 100% DMSO and added to the cells togive a final DMSO concentration of 0.1%. For screening, cells werepre-incubated with test agents for 30 minutes, at a single concentration(10 μM) or at concentrations ranging from 0.001 nM to 10 μM followed byPDGF stimulation (10 ng/mL). Changes in fluorescence at 515 nm weremeasured simultaneously in all 384 wells using a cooled CCD camera. Datawere generated by determining max-min fluorescence levels forunstimulated, stimulated, and drug treated samples. IC₅₀ values for testcompounds were calculated from % inhibition of PDGF stimulated responsesin the absence of inhibitor.

Table II and III present the biodata of some of the compounds of thepresent invention.

TABLE II Biodata of Compounds of the Present Invention with Amide LinkerVEGFR2 VEGFR2 VEGFR1 PDGFβ Cellular Enzyme Enzyme Cellular Example# IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 28 2 8 28 3 28 4 6 29 5 2956 6 5067 12 34 8 8 28 9 30 47 10 46 41 11 28 23 34 12 13 16 27 14 15 33 15 1551 26 73 16 17 21 17 22 20 61 18 10 31 19 30 37 135 20 83 28 21 12 24 3922 18 29 13 105 23 13 35 24 55 24 25 30 25 26 39 120 27 45 66 28 38 5229 18 55 30 29 37 94 31 14 29 20 32 22 46 33 18 56 34 7 70 35 27 29 3610028 37 1005 2610

TABLE 1II Biodata of Compounds of the Present Invention with Urea LinkerVEGFR2 VEGFR2 VEGFR1 PDGFβ Cellular Enzyme Enzyme Cellular Example# IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 38 10 39 23 40 11 41 11 42 60 43 1644 24 45 17 46 2 28 47 107 17 48 16 12 49 145 27 50 5 32 51 16 52 25 5343 28 44 54 130 29 191 55 32 23 26 56 81 20 57 102 45 58 211 36 59 34 2960 27 23 61 91 39 62 122 43 63 111 30 64 16 39 65 15 4 66 17 3 67 31 3168 16 69 24 5 70 2 20 71 20 72 7 15 73 11 74 7 12 76 2 14 3 76 3 14 77 810 78 25 15 4 79 13 38 80 176 69 81 19 82 17 19 83 22 5 84 13 85 6 30 8627 87 5 25 88 374 477 89 5 23 90 8 17 6 21 91 17 14 38 92 37 9 39 93 6 55 14 94 10 6 10 95 30 32 96 3 17 69 97 8 18 98 62 51 99 49 46 100 12 13101 4 8 82 102 10 35 8 103 24 20 104 23 27 105 87 15 106 16 21 107 13 21108 17 14 13 43 109 16 23 110 8 38 10 32 111 13 71 112 13 18 113 23 25114 13 22 115 2 15 2 44 116 12 17 117 6 18 118 22 85 119 12 54 120 43 98121 37 14 20 102 122 142 130 123 13 24 85 124 23 36 125 22 31 126 16 116127 20 21 91 128 10 53 129 12 102 130 5 43 16 32 131 8 31 132 22 15 13366 15 134 4 31 4 135 11 47 136 29 22 137 14 33 138 30 139 14 30 14010000 141 2704 142 111 28 143 16 12 144 28 26 145 10000 10000 146 100007007 147 10000 3505 148 10000 1382

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is NH; R^(I)is selected from the group consisting of

a is 0 or 1; R^(II) is independently selected from the group consistingof hydrogen and NH₂; b is 0 or an integer of from 1 to 2; Y is selectedfrom the group consisting of

and a single bond; Ring A in the structure

is phenyl; R^(III) represents optionally halogen; Z is selected from thegroup consisting of

Ring B in the structure

is selected from the group consisting of: (i′) phenyl; (ii′) thienyl;and (iii′) furoyl; and R^(IV) represents optionally 1-3 substituents,independently selected from the group consisting of methyl and halogen.2.-3. (canceled)
 4. The method according to claim 1, wherein thecompound of Formula I is selected from the group consisting of:({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)aceticacid;methyl({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetate;5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid; methyl5-[4-({3-(3[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate;N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;N-(3-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid;5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylicacid methyl ester; 2,3-dihydroxypropyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;5-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylicacid;5-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylicacid methyl ester; 2-hydroxyethyl5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;2-hydroxyethyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylicacid; methyl5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid; methyl5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylicacid; methyl5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate,3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide;methyl4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate;3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide;5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-hydroxy-1H-pyrrole-3-carboxamide; (S)-5-tert-butyl 1-methyl2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate;1-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylicacid;5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylicacid;N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide;2-hydroxyethyl5-{4-[4-({[(4-chloro-3-(trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate;N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{4-[4-({[(4-chloro-3-(trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide;methy4-(N-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxyl)-S-methylsulfonimidoyl)butanoate;N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide;methyl(2S)-1-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)pyrrolidine-2-carboxylate;N-[dimethyl(oxido)-κ⁴-sulfanylidene]-4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide;1-tert-butyl 2-methyl4-{6-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-1,2-dicarboxylate;1-(4-{[2-amino-6-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-(2-fluoro-5-methylphenyl)urea;1-phenyl-3-{4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]phenyl}urea;1-(2-fluoro-5-methylphenyl)-3-{3-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea;1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-3-yl)pyridin-4-yl]phenyl}urea;and1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea;or a pharmaceutically acceptable salt thereof. 5.-7. (canceled)
 8. Thecompound:

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising at least one compound of claim 1 and at least onepharmaceutically acceptable carrier.
 10. The pharmaceutical compositionof claim 9, wherein the composition comprises of tablets, capsules,creams, gels, ointments, drops, sprays, suspensions, and emulsions. 11.A pharmaceutical composition comprising at least one compound of claim 4and at least one pharmaceutically acceptable carrier.
 12. Thepharmaceutical composition of claim 11, wherein the compositioncomprises of tablets, capsules, creams, gels, ointments, drops, sprays,suspensions, and emulsions.
 13. A pharmaceutical composition comprisingat least one compound of claim 8 and at least one pharmaceuticallyacceptable carrier.
 14. The pharmaceutical composition of claim 13,wherein the composition comprises of tablets, capsules, creams, gels,ointments, drops, sprays, suspensions, and emulsions.
 15. A method oftreating a disease or condition in a human subject, wherein said diseaseor condition is selected from the group consisting of diabeticretinopathy, macular degeneration, age-related macular degeneration, andretinopathy of prematurity, comprising administering to said humansubject a therapeutically effective amount of at least one compound ofclaim 1 or a pharmaceutically acceptable salt thereof.
 16. The method ofclaim 15, wherein said administration is through intravitreal injection,subtenon injection, ophthalmic bioerodible implant, non-bioerodibleophthalmic insert and depots.
 17. A method of treating a disease orcondition in a human subject, wherein said disease or condition isselected from the group consisting of diabetic retinopathy, maculardegeneration, age-related macular degeneration, and retinopathy ofprematurity, comprising administering to said human subject atherapeutically effective amount of at least one compound of claim 4 ora pharmaceutically acceptable salt thereof.
 18. The method of claim 17,wherein said administration is through intravitreal injection, subtenoninjection, ophthalmic bioerodible implant, non-bioerodible ophthalmicinsert and depots.
 19. A method of treating a disease or condition in ahuman subject, wherein said disease or condition is selected from thegroup consisting of diabetic retinopathy, macular degeneration,age-related macular degeneration, and retinopathy of prematurity,comprising administering to said human subject a therapeuticallyeffective amount of at least one compound of claim 8 or apharmaceutically acceptable salt thereof.
 20. The method of claim 19,wherein said administration is through intravitreal injection, subtenoninjection, ophthalmic bioerodible implant, non-bioerodible ophthalmicinsert and depots.